Additional clinical studies will be required to support the approval of Forest/Replidyne's antibiotic Orapem (faropenem medoxomil) in all four proposed indications: acute bacterial sinusitis, community-acquired pneumonia, acute exacerbation of chronic bronchitis and uncomplicated skin and skin structure infections. The companies announced Oct. 23 that they had received an FDA "not approvable" letter for the drug Oct. 20.

It will take a minimum of two years to complete the appropriate studies, the companies reported.

"We are discussing the FDA findings and recommendations with Forest, and they have expressed their continued support at this time for the further development and commercialization of faropenem," Replidyne CEO Kenneth Collins stated during an Oct. 23 conference call. "We continue to believe that faropenem has the potential to be a safe, efficacious and well tolerated treatment option for patients."

The companies said they will be discussing next steps with FDA in the coming months, including the number and design of trials that would be required for approval.

FDA's decision not to approve the drug reflects the agency's new opinion on the need for superiority data to support antibiotic approvals, Replidyne said. The agency is requiring superiority studies for the approval of faropenem, and the NDA submission was based largely on non-inferiority studies following consultation with the FDA.

"Historically, the FDA has not required superiority design studies such as placebo-controlled studies for approval for antibiotics," Collins stated. "We and Forest believe that recent public FDA statements over the need for placebo-controlled studies for antibiotics were a factor in its decision."

FDA's handling of antibiotics like Sanofi-Aventis' Ketek (telithromycin) and Bristol-Myers Squibb's now-discontinued Tequin (gatifloxacin) have come under increased scrutiny from legislators and public health groups recently over safety and efficacy concerns (¹ Also see "Sanofi’s Ketek Is New Target Of Congressional Scrutiny Of FDA" - Pink Sheet, 2 May, 2006.).

More recently, legislators requested a Government Accountability Office report on FDA's use of non-inferiority trials, specifically mentioning Ketek in the request.

For Orapem, Replidyne said it will likely need to conduct superiority studies for the ABS and ACEB indications. For the CAP indication, studies confirming bacterial infection and additional microbiologic analysis will be required. An additional study comparing faropenem to current standard of care will also be necessary for the SSSI indication.

FDA did not raise any safety, chemistry, manufacturing or controls issues related to the drug, the firm added. The NDA submission was based on the results of 11 Phase III clinical trials involving more than 5,000 patients. In addition, Replidyne currently has two trials ongoing, a placebo-controlled Phase III study for AECB and a Phase II pediatric study.

Replidyne is also developing a pediatric suspension formulation of Orapem. The Louisville, Colo.-based firm has pointed to the pediatric anti-infective market as one of its key long-term goals for growing the Orapem line.

Under Replidyne's contractual agreement with Forest, faropenem must receive approval for at least two indications. The company said the contract also calls for Forest to pay the "lion's share" of the ongoing clinical trial work.

In July, Forest President Ken Goodman said the company was anticipating approval of the sinusitis and CAP indications initially. An approval would mark Forest's entry into the antibiotic market; the company signed a licensing deal with Replidyne for Orapem in February (² Also see "Forest Enters Antibiotic Field Through Faropenem Licensing Deal" - Pink Sheet, 13 February, 2006.).

Replidyne submitted the NDA for the antibiotic in December, marking the Louisville, Colo. biotech's first submission (³ Also see "Orapem NDA Is Replidyne’s First" - Pink Sheet, 9 January, 2006.).

- Jessica Merrill (j.merrill@elsevier.com)

Forest’s Faropenem Is “Not Approvable”; Additional Studies Will Take Two Years

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