Washington Editor

The FDA rejected Replidyne Inc.'s new drug application for the antibiotic faropenem, causing the company's shares to lose 45 percent of their value on Monday.

The stock (NASDAQ:RDYN) fell $4.65 on heavy trading to close at $5.59. Shares in Replidyne's partner, Forest Laboratories Inc., also fell on the news.

In the non-approvable letter, the FDA asked for further clinical studies and is raising the bar in the process, calling for superiority trials even though the data underlying the NDA came from non-inferiority studies that had the agency's blessing in the past. All currently marketed antibiotics were approved based on that standard, but there's clearly a new direction. The companies plan to comply, which would satisfy the shift to more rigorous antibiotic trial designs in certain indications that aren't immediately life threatening, but the extra tests will delay faropenem by a minimum of two years.

"This is a recent transition," Replidyne Chief Medical Officer Roger Echols said of the evolution in the FDA's thinking, "and we got caught in the change."

It's the result of a statistical argument that non-inferiority studies "can't define the margin of benefit," he told BioWorld Today, because the advantage of treatment compared to non-treatment hasn't been established. That was essentially the basis of an FDA advisory committee rejection of an application to expand the use of Factive (gemifloxacin, from Oscient Pharmaceuticals Corp.) in acute bacterial sinusitis (ABS). (See BioWorld Today, Sept. 13, 2006.)

The faropenem NDA was filed in December with findings from 11 Phase III trials in four indications: ABS, community-acquired pneumonia (CAP), acute exacerbation of chronic bronchitis (AECB) and uncomplicated skin and skin-structure infections (SSSI). They all met their clinical endpoints, but they all were non-inferiority studies.

An additional microbiologic evaluation could be required for CAP, and for ABS and AECB, superiority studies might be needed. Such trials, Echols said, would be "more difficult" for a number of reasons related to the feasibility and ethics of such studies.

Among them, trial size and patient recruitment represent daunting challenges. Louisville, Colo.-based Replidyne already is conducting a placebo-controlled Phase III study in AECB, but it has had enrollment troubles. Echols said the "majority" of investigators asked to participate refused, and the protocol was turned down by several ethics committees and health agencies. To make it "attractive enough," he said, the trial includes an active control in addition to placebo, and it's designed to be overpowered and overenrolled.

Besides such recruitment problems, the placebo arm could prove damaging for another reason: high placebo response rates. That's what analyst Joshua Schimmer of Cowen and Co. said in a research note, labeling superiority studies in AECB or ABS as worrisome and expressing a "lack of confidence" in the ability of faropenem or any other antibiotic to demonstrate superiority over placebo in those indications. He said he foresees the drug's launch being delayed until at least 2010.

Replidyne President and CEO Kenneth Collins pointed to a coming FDA meeting to "really discuss" what the next steps will look like, a gathering that is not yet scheduled but also will include Forest representatives. For now, the New York pharmaceutical firm's management has said it would stick with the partnership, though faropenem needs at least two respiratory tract approvals to maintain the contractual relationship, and that rejection raises questions about the deal's prospects.

Collins told BioWorld Today he could provide more clarity on future trial designs after that FDA discussion, including the number of trials needed for each indication and whether they'll be run in parallel. It's possible they could use a higher dose - the current Phase III trial is testing 600 mg, double the dose in the previous 11 - and higher doses could allow for shorter durations of treatment. In addition, inclusion criteria likely would be strict to ensure a high rate of patients with true bacterial infections. Not surprisingly, Collins said he'd like them to be "as small as possible" and completed "as quickly as possible."

Forest funds a "significant majority" of faropenem's clinical development costs, Replidyne Chief Financial Officer Mark Smith told BioWorld Today, adding that Replidyne has $134 million in reserve for its obligations.

The drug is a member of the penem subclass of beta-lactam antibiotics, which Collins characterized as generally safe and well tolerated with a broad spectrum of activity. He added that he "continues to believe" in the safety and effectiveness of faropenem, which also is the subject of a Phase II pediatric study in acute otitis media.

The FDA did not raise any safety concerns about the drug - there is a database of such information in more than 5,000 patients - and the agency had no issues with the product's chemistry, manufacturing or controls.

Adeza Sinks On Action Letter

Adeza Biomedical Corp. received an approvable letter on its NDA for Gestiva, a long-acting form of a naturally occurring progesterone for the prevention of preterm birth in women with a history of preterm delivery.

The news dropped the company's shares (NASDAQ:ADZA) by 16.4 percent on Monday, or $2.94, to close at $14.99.

The FDA is asking for an additional animal study and certain other conditions, and its action letter also outlines post-approval clinical requirements that are consistent with recommendations made by an advisory committee in August. Adeza, of Sunnyvale, Calif., is seeking orphan drug designation for Gestiva and plans to meet with the agency to provide additional new information for further review.