FDA advisory committee recommends new indication for IV daptomycin

April 2006

The FDA’s Anti-Infective Drugs Advisory Committee (AIDAC) unanimously voted that there is substantial safety and efficacy evidence to recommend a new indication for daptomycin for injection (Cubicin, Cubist Pharmaceuticals) to treat patients with Staphylococcus aureus bacteremia. However, the committee was split 5-4 over whether daptomycin should be indicated for infective endocarditis.

AIDAC members recently reviewed phase-3 trial results, in which daptomycin as monotherapy at 6 mg/kg met its primary endpoints for noninferiority vs. dual therapy standard of care for treatment of S. aureus bacteremia and infective endocarditis.

“Patients with infections of the bloodstream and heart caused by S. aureus are seriously ill and pose treatment challenges. These challenges are particularly significant when the infection is caused by methicillin-resistant S. aureus, or MRSA,” said G. Ralph Corey, MD, professor of medicine and infectious diseases at Duke University Medical Center and director of infectious diseases at Duke Clinical Research Institute.

Corey, chair of the Independent External Adjudication Committee (IEAC), was one of five infectious disease experts, who, blinded to therapy, assessed outcomes for all patients in the phase-3 trials.

The AIDAC vote is not binding on the FDA’s decision for the IV daptomycin Supplemental New Drug Application (SNDA).

Applying for SNDA

Cubist submitted the SNDA on Sept. 26, 2005, requesting a new indication for treatment of patients with bacteremia with known or suspected endocarditis caused by S. aureus. On Nov. 21, the FDA granted the application priority review. Last month the FDA issued an “approvable letter” for the SNDA.

“The committee’s vote is further validation of the robust and consistent results of our pivotal trial,” said Mike Bonney, president and chief executive officer of Cubist.

Daptomycin is the only once-daily bactericidal antibiotic approved in the United States. It was approved in 2003 and is indicated for the treatment of complicated skin and skin structure infections caused by susceptible strains of S. aureus, including MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae and Enterococcus faecalis.

Phase-3 trial results

The committee reviewed findings from a multicenter, randomized, open-label phase-3 study that evaluated the safety and efficacy of daptomycin in 236 patients with S. aureus infective endocarditis or bacteremia studied at 38 sites in the United States and six sites in Europe. Results showed that daptomycin is comparable to dual therapy standard of care for patients with these infections caused by MRSA or susceptible strains. The study met its primary endpoints of noninferiority vs. the current standard-of-care treatments.

Researchers randomized patients to receive either daptomycin monotherapy at 6 mg/kg once daily, or dual therapy standard of care with either 1 g of vancomycin twice daily plus initial gentamicin for methicillin-resistant infections or 2 g of nafcillin 6 times daily for methicillin-susceptible infections plus initial gentamicin.

IEAC members assessed outcome at end of therapy and test of cure. Primary efficacy endpoints were IEAC-determined success at test of cure in the intent-to-treat population (ITT) and the per protocol population.

The ITT population consisted of 235 patients and the per protocol population consisted of 139 patients. In the ITT population, 23% had S. aureus endocarditis and 51% had complicated S. aureus bacteremia. Researchers found MRSA in 37% of the daptomycin-treated patients and 38% of the comparator arm patients. In the ITT analysis, success rates at end of therapy were 61.7% for the daptomycin group vs. 60.9% in the comparator arm. Test of cure rates were 44.2% in the daptomycin group vs. 41.7% in the comparator arm. In the ITT MRSA patient subpopulation, success rates were 44.4% for daptomycin vs. 31.8% for the comparator regimen. In the protocol population analysis, success rates at test of cure were 54.4% in the daptomycin group and 53.3% in the comparator arm. Overall survival rates were 85% in the daptomycin and 84% in the comparator arms.

The incidence of reported adverse events, was similar for both arms. Adverse events leading to discontinuation of treatment included CPK elevation in 2.5% (3/120) of daptomycin-treated patients, and renal impairment in 4.3% (5/116) in comparator-treated patients.

Infective endocarditis data

Of the total 235 patients in the ITT population, all with S. aureus of the bloodstream, 53 patients were diagnosed with infective endocarditis. Researchers randomized all patients to receive either IV daptomycin or a comparator regimen of vancomycin, plus initial low-dose gentamicin if the patient had MRSA, or a synthetic penicillin, plus initial low-dose gentamicin, if the patient had methicillin susceptible S. aureus.

Forty-two percent (8 of 19) of patients taking IV daptomycin with a final diagnosis of right-sided endocarditis were asymptomatic compared with 43.8% (7 of 16) of those taking the comparator regimen with a final diagnosis of right-sided endocarditis. Of the patients with a final diagnosis of left-sided endocarditis, most failed, regardless of therapy, only one of nine patients who received daptomycin and two of nine who received a comparator regimen were asymptomatic.

Due to these findings, the AIDAC felt that labeling should indicate that researchers have studied IV daptomycin in patients with infective endocarditis. “Some committee members suggested that labeling should state that if daptomycin “is to be used in the treatment of infective endocarditis, the patients should be monitored very carefully for treatment failures.”

For more information:

• Fowler V, Cosgrove S, Abrutyn E. Daptomycin vs. standard therapy for Staphylococcus aureus bacteremia (SAB) and infective endocarditis (SAIE). Late-Breaker Abstract K-426a. Presented at: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; Dec. 16-19, 2005; Washington.
• Cubist’s background package and the FDA briefing document are available at www.fda.gov/ohrms/dockets/ac/cder06.html#AntiInfective.