Advanced Life Sciences has not given up on developing its investigational drug Restanza (cethromycin) for community acquired pneumonia, despite a June 2 recommendation by the FDA Anti-infective Drugs Advisory Committee that the drug should not be approved for CAP due to lack of efficacy.

Committee members did suggest that the drug might be useful to develop for emerging antibiotic-resistant infectious diseases, especially to treat the increasing ranks of macrolide-resistant pneumonia. Restanza is a second-generation ketolide for once-daily oral administration.

"I think that this is a mediocre drug. The place for it is in the realm of resistant organisms. To me that is the only road forward," committee member Kent Sepkowitz, Memorial Sloan-Kettering Cancer Center, said after the committee voted 11-3 with one abstention that ALS did not prove efficacy.

Caught In Changing Drug Development Standards

FDA standards for clinical trials to develop anti-infectives have been evolving for several years (see ¹ Also see "CAP Drugs Must Meet Stricter Noninferiority Criteria Under Draft FDA Guidance" - Pink Sheet, 8 June, 2009.). Indeed, the FDA Amendments Act of 2007 required new guidances on drug development for several bacterial respiratory illnesses.

Cethromycin's NDA was supported by two pivotal noninferiority studies that compared cethromycin to clarithromycin (Abbott's Biaxin and generics) with a primary endpoint of clinical cure rate. At least 1,100 patients received one drug dose (² Also see "Advanced Life Sciences’ Cethromycin Faces Anti-Infectives Panel With Solid Data" - Pink Sheet, 29 May, 2009.).

A ³ draft guidance issued by FDA March 19 suggests that if firms are using a noninferiority trial, the margin should be less than 10 percent. Where the guidance specifications differ from the standards used by ALS is in the patient selection criteria (the new guidance wants patients with severe disease), more patients whose bacteria are identified through microbiology and no patients who had received another antibiotic near the time they receive the study medication.

ADL's analysis of the clinical trials for cethromycin showed that the drug met the 10 percent noninferiority test against clarithromycin. An integrated analysis showed that in the ITT population, the clinical cure rate was 83 percent in the cethromycin group compared with 84.8 percent for clarithromycin.

But once FDA reviewers applied criteria from the new guidance to the ALS study data, it eliminated nearly half of the original intent to treat populations. With that much smaller number, the noninferiority margins were inadequate.

FDA also said that results appeared inconsistent between the two studies and that there was an indication, at least in one study, that the population was "at very low risk."

But the clincher was FDA reviewer Christopher Kadoorie's statement that ALS had an outdated study design.

"The sponsor's proposed noninferiority margin approach, known as a sliding scale approach, is no longer considered acceptable by the FDA. This approach was based on the 1992 'Points To Consider' document," he said.

"However, the FDA had posted a disclaimer to this document in February 2001, stating the sliding scale approach is no longer in use."

Those comments appeared to have a strong influence on committee members.

"The new rules are the ones that should be applied," said Dean Follmann, Chief, Biostatistics Branch, National Institute of Allergy and Infectious Diseases. "The old rules' [noninferiority] margins were just too wide and unacceptable. The FDA's analyses were very insightful in this regard," he noted.

Committee chair Thomas Moore, University of Kansas, said, "It seems inherently unfair to judge this drug by new rules." However, he agreed that it is difficult to use the small numbers to reliably assess noninferiority.

That didn't stop investors from crying "foul". "The inherent unfairness of holding this company and product to a post hoc standard could be a factor in an FDA decision to approve the product on its July 31, 2009, user fee date," wrote Ira Loss, an analyst with Washington Analysis, in a June 2 FDA Update.

Loss called the decision "the ultimate 'gotcha.'"

The anti-infectives advisory committee meeting, like an FDA panel meeting for diabetes products earlier this year, serves as a test case for how the agency will apply its new development criteria for already pending products.

Other drugs in development for CAP include Wyeth's Tygacil (tigecycline), which received an "approvable" letter last June; Johnson & Johnson's ceftobiprole, which received a "complete response" letter in December; and Forest's ceftaroline, for which an NDA filing is planned later this year.

For cethromycin, safety data indicate the drug is safe and well tolerated, with the most commonly reported events including dysgeusia (metallic taste), diarrhea, nausea and headache.

FDA agreed in general with the safety data, and the committee voted 11-3, with one abstention, that the studies demonstrated the safety of cethromycin in the treatment of mild to moderate CAP.

Moving Forward With Biodefense Applications

During a June 3 conference call to discuss the committee's recommendations, investors and ALS officials voiced surprise that FDA would have given the firm the go-ahead in 2005 to conduct the Phase III studies using the sliding scale.

But CEO Michael Flavin and Chief Financial Officer John Flavin said they were pleased that the safety data were confirmed. The firm will move forward to help FDA finish its review and continue to develop the drug for biodefense purposes.

ALS has a lot on the line with cethromycin because its financial house is in a tenuous position. Flavin said the firm has about $2 million in cash and is actively seeking a development partner. The firm licensed Asia Pacific rights (except in Japan, which Abbott still owns) to Wyeth in October for an equity stake, netting ALS about $1.7 million.

- Pamela Taulbee (p.taulbee@elsevier.com)

Advanced Life Sciences Restanza Blocked By New FDA Efficacy Criteria

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