Last week's jolting decision by the FDA to turn thumbs down on Replidyne Inc.'s new drug application for the antibiotic Orapem (faropenem) clipped shares by 45 percent and put the fear into companies with similar drugs that might get swept into what appears to be a sea change in policy.

FDA officials "have been saying they're going to update their guidelines in the near term for two or three years," said Matthew Osborne, analyst with Lazard Capital Markets. "What they've continued to tell [trial] sponsors is that they'd like to have a placebo-controlled or superiority study, but you can submit the data you have in hand."

The agency wants more trials with Orapem, beyond the noninferiority studies that formed the basis of the drug's NDA - as well as the NDAs for every currently approved antibiotic - which means a delay of at least two years for Replidyne's product, partnered with Forest Pharmaceuticals Inc.

Regulators, alarmed by the growing resistance to antibiotics, suddenly are motivated by the idea that non-inferiority studies cannot accurately show the extent of benefit, because the advantage of treatment compared to lack of treatment has not been proved. "They need to understand how a patient resolves over time, who is treated with nothing," Osborne said.

Evidence of the FDA's shift regarding antibiotics came last month, when an FDA advisory panel rejected a plan to expand the use of Factive (gemifloxacin), from Oscient Pharmaceuticals Corp., in acute bacterial sinusitis (ABS). Already cleared as a five-day treatment for acute bacterial exacerbations of chronic bronchitis and community-acquired pneumonia (CAP) over a seven-day treatment course, Factive reaped $11.9 million in the first six months of this year, and likely will do better during the cooler months.

Oscient based Factive's bid on multiple noninferiority trials. The supplemental new drug application for sinusitis includes data from five Phase III trials that were conducted by Factive's former owner, London-based GlaxoSmithKline plc.

The Orapem NDA, filed in December, included findings from 11 Phase III, noninferiority trials in four indications: ABS, CAP, acute exacerbation of chronic bronchitis (AECB) and uncomplicated skin and skin-structure infections (SSSI). All met their clinical endpoints. Replidyne officials said the agency might demand more microbiologic evaluation for CAP, and superiority studies for ABS and AECB.

Replidyne already is conducting a placebo-controlled Phase III study in AECB, but it has met enrollment troubles. Most investigators who were asked to participate refused. Ethics committees and health agencies nixed the protocol. Even if the trial goes ahead, using a placebo arm could make it fail, if non-drug response rates prove strong - as they very well might, since as much as 40 percent of such cases (maybe more) are caused by viruses, and patients manage to resolve their illness without medication. That's true of ABS, too.

But the market for outpatient antibiotics is "driven by patient demand," Osborne said. "They come into the office, and they want to walk away with a prescription in hand." A patient with a virus might take the full course of antibiotics without needing them, thus boosting the resistance problem for no reason.

"The market's in desperate need of a rapid, cost-effective diagnostic test," Osborne said. "That's not on the horizon for the next five or seven years." Nor are breakthroughs in antibiotic work likely due soon, he said.

Another possible target of the FDA's new thinking: cethromycin, the compound from Advanced Life Sciences Holdings Inc., which this month reported data at the Infectious Disease Society of America meeting in Toronto comparing the safety and efficacy of the drug at varying doses for ABS. A Phase III trial in AEBC for adult use is ongoing. At another prestigious scientific meeting, the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, the firm said data with the second-generation ketolide antibiotic showed safety and efficacy at multiple dose levels in CAP, AECB and anthrax.

To get a sense of how serious the FDA change in attitude toward antibiotics might be, Lazard hosted a conference call with pulmonologists, focused specifically on Orapem, Factive and cethromycin.

Doctors noted that many would back away from placebo-controlled studies, especially if a sinus tap (sampling of mucus by needle) is involved. But because of the possible viral cause in ABS and AECB, such a study might be the only viable route.

"Endpoints, such as time to next exacerbation and rapidity in resolution of symptoms, could circumvent the difficulty of enrolling patients and still help to identify a truly differentiated antibiotic," Osborne wrote in a research report. "Broadly speaking and in the long-term, physician overabuse of antibiotics may wane, but patient demand will continue to drive prescriptions."

The good news for some companies is that physicians consulted by Lazard agreed the goal posts for CAP, at least, remain at the same distance, and the FDA is not likely to insist on placebo-controlled trials in that indication because of ethical reasons, given the severity of infection compared to ABS and AECB. That bodes well for cethromycin, since its owner has a noninferiority protocol in place, Osborne noted.

As for the market chances with each of the drugs, doctors consulted by Lazard didn't like Factive's rash stigma. (The FDA panel pointed to similar concerns, and even fretted over the possibility of Stevens-Johnson syndrome, a sometimes-fatal rash.) Physicians also noted the potential for causing cross-resistance (or cross-rash reactions) to other fluoroquinolones. Levaquin (levofloxicin) from Johnson & Johnson is likely to keep its dominant position in the quinolone class.

For Orapem, sinusitis and otitis media stand as the most appealing indications, the physicians said, in which cethromycin could work as a "safer Ketek," referring to the brand name for telithromycin, from Sanofi-Aventis Group. Ketek became the first ketolide approved in the U.S. in April 2004, but recently was found to carry the risk of liver toxicity.

Osborne said Ketek "went through an extensive review and two panels" previously, and still shows problems. "Clinicians tend to think that, out of 2 million-plus prescriptions, the rate is not overwhelming, but there is some [toxicity] signal there," he said. "Even post-approval, there's a lot of uncertainty." In January, the FDA issued a warning about Ketek (approved by the FDA in April 2004 for the treatment of pneumonia, bacterial bronchitis and sinusitis).

Ketek was not center stage last week, though, when the growing problem of antibiotic resistance - possibly caused by patients' demand for antibiotics they don't need - collided for the second time recently with the efforts of drug firms to develop still more drugs. "There are not a lot of outpatient antibiotics in development right now," Osborne said. "When the well dries up and there's nothing left, the FDA will decide with the industry and patient advocacy groups what's the best step going forward."

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