FDA panel unanimously supports tedizolid phosphate for severe skin infections

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously in support of the approval of the antibacterial drug tedizolid phosphate for acute bacterial skin and skin structure infections (ABSSSI).

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 14-0 that tedizolid phosphate (Sivextro), made by Cubist Pharmaceuticals, is safe and effective for the treatment of ABSSSI caused by susceptible isolates of the designated microorganisms. Patients in the firm’s phase III study received a daily 200 mg dose of the antibacterial drug for six days either orally or intravenously.

The firm is seeking a proposed indication of ABSSSI caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] variations), Streptococcus pyogenes, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, the Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus), and Enterococcus faecalis. ABSSSI also includes cellulitis/erysipelas, major cutaneous abscess with surrounding erythema, and wound infection.

The phase III study consisted of two trials: study TR701-112 and study TR701-113. Both studies were global, multicenter, randomized, active-controlled, double-blind, double-dummy noninferiority trials. Subjects in both studies were stratified according to geographic region and one of three different clinical syndromes: cellulitis/erysipelas, major cutaneous abscesses, and wound infections. The first study was also stratified by the presence or absence of fever at baseline.

Study TR701-12 compared 6 days of oral tedizolid phosphate 200 mg daily with 10 days of oral linezolid 600 mg twice daily for the treatment of ABSSSI. Study TR701-113 differed in that patients were stratified either to 6 days of 200 mg IV or oral tedizolid phosphate and 10 days of twice daily 600 mg IV or oral linezolid. Subjects were required to receive at least two IV doses, and then had the option to switch to oral medication provided certain pre-specified criteria were met.

The primary endpoint of each study was the percentage of patients who responded during early clinical evaluation at the 48-72 hour visit in the intent-to-treat population. However, the two studies’ primary endpoints were measured differently because the first study protocol was designed prior to 2010 FDA draft guidance on ABSSSI drugs, and the second study protocol was designed to match the 2013 final FDA guidance.

The first study’s primary endpoint was no increase in lesion surface area from baseline and oral temperature of less than or equal to 36.7 degrees Celsius, confirmed by a second temperature measurement within 24 hours. (JAMA 2013;309:559-9 [doi:10.1001/jama.2013.241]).

The second study’s primary endpoint was greater than or equal to a 20% reduction in lesion area of erythema, edema and/or induration (length X width), compared with baseline.

In both studies, 6 days of once-daily tedizolid was noninferior to 10 days of twice-daily linezolid. Both studies also met their first secondary endpoint of clinical response at end-of-therapy visit (day 11) in the intent-to-treat population, and the second secondary endpoint of achieving investigator’s assessment of clinical success at the post therapy evaluation visit in the intent-to-treat population.

Overall, the panel found the drug to be safe and efficacious, offering clinicians another antibiotic option for patients.

"The reason I voted yes is, given the favorable comparison against the comparator linezolid, it offers the benefit of a shorter course of therapy, less frequent doses per day, and there appears to be an equivalency in the kind and the severity of side effects," said Dr. Thomas A. Moore of the department of medicine at the University of Kansas, Wichita.

In terms of labeling, the panel advised against including children aged 12-18 years in the drug’s indication, and recommended additional studies of the drug’s safety and efficacy in this population. The panel also recommended a post-market study of the long-term safety of the drug beyond 6 days of use.

Dr. Moore also recommended noting the number of gastrointestinal side effects in the trial.

"The labeling would have to address the rather frequent number of adverse effects. I was surprised to see the analysis that at least half of the patients had gastrointestinal symptoms," he said. "Nevertheless, this is a clearly effective drug and one which will add to our armamentarium against resistant organisms."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously in support of the approval of the antibacterial drug tedizolid phosphate for acute bacterial skin and skin structure infections (ABSSSI).

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 14-0 that tedizolid phosphate (Sivextro), made by Cubist Pharmaceuticals, is safe and effective for the treatment of ABSSSI caused by susceptible isolates of the designated microorganisms. Patients in the firm’s phase III study received a daily 200 mg dose of the antibacterial drug for six days either orally or intravenously.

The firm is seeking a proposed indication of ABSSSI caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] variations), Streptococcus pyogenes, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, the Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus), and Enterococcus faecalis. ABSSSI also includes cellulitis/erysipelas, major cutaneous abscess with surrounding erythema, and wound infection.

The phase III study consisted of two trials: study TR701-112 and study TR701-113. Both studies were global, multicenter, randomized, active-controlled, double-blind, double-dummy noninferiority trials. Subjects in both studies were stratified according to geographic region and one of three different clinical syndromes: cellulitis/erysipelas, major cutaneous abscesses, and wound infections. The first study was also stratified by the presence or absence of fever at baseline.

Study TR701-12 compared 6 days of oral tedizolid phosphate 200 mg daily with 10 days of oral linezolid 600 mg twice daily for the treatment of ABSSSI. Study TR701-113 differed in that patients were stratified either to 6 days of 200 mg IV or oral tedizolid phosphate and 10 days of twice daily 600 mg IV or oral linezolid. Subjects were required to receive at least two IV doses, and then had the option to switch to oral medication provided certain pre-specified criteria were met.

The primary endpoint of each study was the percentage of patients who responded during early clinical evaluation at the 48-72 hour visit in the intent-to-treat population. However, the two studies’ primary endpoints were measured differently because the first study protocol was designed prior to 2010 FDA draft guidance on ABSSSI drugs, and the second study protocol was designed to match the 2013 final FDA guidance.

The first study’s primary endpoint was no increase in lesion surface area from baseline and oral temperature of less than or equal to 36.7 degrees Celsius, confirmed by a second temperature measurement within 24 hours. (JAMA 2013;309:559-9 [doi:10.1001/jama.2013.241]).

The second study’s primary endpoint was greater than or equal to a 20% reduction in lesion area of erythema, edema and/or induration (length X width), compared with baseline.

In both studies, 6 days of once-daily tedizolid was noninferior to 10 days of twice-daily linezolid. Both studies also met their first secondary endpoint of clinical response at end-of-therapy visit (day 11) in the intent-to-treat population, and the second secondary endpoint of achieving investigator’s assessment of clinical success at the post therapy evaluation visit in the intent-to-treat population.

Overall, the panel found the drug to be safe and efficacious, offering clinicians another antibiotic option for patients.

"The reason I voted yes is, given the favorable comparison against the comparator linezolid, it offers the benefit of a shorter course of therapy, less frequent doses per day, and there appears to be an equivalency in the kind and the severity of side effects," said Dr. Thomas A. Moore of the department of medicine at the University of Kansas, Wichita.

In terms of labeling, the panel advised against including children aged 12-18 years in the drug’s indication, and recommended additional studies of the drug’s safety and efficacy in this population. The panel also recommended a post-market study of the long-term safety of the drug beyond 6 days of use.

Dr. Moore also recommended noting the number of gastrointestinal side effects in the trial.

"The labeling would have to address the rather frequent number of adverse effects. I was surprised to see the analysis that at least half of the patients had gastrointestinal symptoms," he said. "Nevertheless, this is a clearly effective drug and one which will add to our armamentarium against resistant organisms."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously in support of the approval of the antibacterial drug tedizolid phosphate for acute bacterial skin and skin structure infections (ABSSSI).

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 14-0 that tedizolid phosphate (Sivextro), made by Cubist Pharmaceuticals, is safe and effective for the treatment of ABSSSI caused by susceptible isolates of the designated microorganisms. Patients in the firm’s phase III study received a daily 200 mg dose of the antibacterial drug for six days either orally or intravenously.

The firm is seeking a proposed indication of ABSSSI caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] variations), Streptococcus pyogenes, Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, the Streptococcus anginosus group (including S. anginosus, S. intermedius and S. constellatus), and Enterococcus faecalis. ABSSSI also includes cellulitis/erysipelas, major cutaneous abscess with surrounding erythema, and wound infection.

The phase III study consisted of two trials: study TR701-112 and study TR701-113. Both studies were global, multicenter, randomized, active-controlled, double-blind, double-dummy noninferiority trials. Subjects in both studies were stratified according to geographic region and one of three different clinical syndromes: cellulitis/erysipelas, major cutaneous abscesses, and wound infections. The first study was also stratified by the presence or absence of fever at baseline.

Study TR701-12 compared 6 days of oral tedizolid phosphate 200 mg daily with 10 days of oral linezolid 600 mg twice daily for the treatment of ABSSSI. Study TR701-113 differed in that patients were stratified either to 6 days of 200 mg IV or oral tedizolid phosphate and 10 days of twice daily 600 mg IV or oral linezolid. Subjects were required to receive at least two IV doses, and then had the option to switch to oral medication provided certain pre-specified criteria were met.

The primary endpoint of each study was the percentage of patients who responded during early clinical evaluation at the 48-72 hour visit in the intent-to-treat population. However, the two studies’ primary endpoints were measured differently because the first study protocol was designed prior to 2010 FDA draft guidance on ABSSSI drugs, and the second study protocol was designed to match the 2013 final FDA guidance.

The first study’s primary endpoint was no increase in lesion surface area from baseline and oral temperature of less than or equal to 36.7 degrees Celsius, confirmed by a second temperature measurement within 24 hours. (JAMA 2013;309:559-9 [doi:10.1001/jama.2013.241]).

The second study’s primary endpoint was greater than or equal to a 20% reduction in lesion area of erythema, edema and/or induration (length X width), compared with baseline.

In both studies, 6 days of once-daily tedizolid was noninferior to 10 days of twice-daily linezolid. Both studies also met their first secondary endpoint of clinical response at end-of-therapy visit (day 11) in the intent-to-treat population, and the second secondary endpoint of achieving investigator’s assessment of clinical success at the post therapy evaluation visit in the intent-to-treat population.

Overall, the panel found the drug to be safe and efficacious, offering clinicians another antibiotic option for patients.

"The reason I voted yes is, given the favorable comparison against the comparator linezolid, it offers the benefit of a shorter course of therapy, less frequent doses per day, and there appears to be an equivalency in the kind and the severity of side effects," said Dr. Thomas A. Moore of the department of medicine at the University of Kansas, Wichita.

In terms of labeling, the panel advised against including children aged 12-18 years in the drug’s indication, and recommended additional studies of the drug’s safety and efficacy in this population. The panel also recommended a post-market study of the long-term safety of the drug beyond 6 days of use.

Dr. Moore also recommended noting the number of gastrointestinal side effects in the trial.

"The labeling would have to address the rather frequent number of adverse effects. I was surprised to see the analysis that at least half of the patients had gastrointestinal symptoms," he said. "Nevertheless, this is a clearly effective drug and one which will add to our armamentarium against resistant organisms."