FDA panel endorses antibacterial dalbavancin

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."