Larry Hand
The Anti-Infective Drugs Advisory Committee of the US Food and Drug Administration (FDA) has voted unanimously to recommend approval of 2 new antibacterial agents for the treatment of skin and skin structure infections caused by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA).
The 2 drugs are tedizolid phosphate (Sivextro, Cubist Pharmaceuticals, Inc), and dalbavancin (Dalvance, Durata Therapeutics, Inc).
Each drug has gone through two phase 3 noninferiority clinical trials and has been considered for approval under the Generating Antibiotic Incentives Now (GAIN) initiative signed into law in 2012 as part of the Food and Drug Safety and Innovation Act. The incentive was designed to support development of new antibacterial drugs.
Although both approval recommendations were unanimous votes, they did not come without strong opposition during the public hearings portion of the committee meeting.
Tedizolid
Tedizolid is a once-daily oxazolidinone prodrug that inhibits protein synthesis by binding to bacteria, and is active against gram-positive pathogens. The proposed indication for tedizolid, which can be administered orally or intravenously (IV), is for treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by gram-positive pathogens, including MRSA, methicillin-susceptible S. aureus (MSSA), and Streptococcus pyogenes.
The clinical development program for tedizolid included two phase 3 randomized, double-blind, noninferiority clinical trials comparing tedizolid with linezolid (Zyvox, Pfizer), the only FDA-approved drug for MRSA- and MSSA-related infections with the IV-to-oral switch capability. Trial results were published last year, as reported by Medscape Medical News . Patients had cellulitis, abscess, or traumatic injury.
The first trial involved 667 patients randomly assigned to receive oral 200 mg of tedizolid once daily for 6 days and 658 patients randomly assigned to receive 600 mg linezolid twice daily for 10 days. The second trial involved 666 patients randomly assigned to receive oral tedizolid once a day for 6 days and 658 patients randomly assigned to receive oral 200 mg IV for 6 days with the option of switching to oral 600 mg of linezolid twice daily for 10 days.
Researchers found that, for the first trial, tedizolid met the primary endpoint of cessation of lesion spread at 48 to 72 hours after first treatment for 79.5% of patients in its group, compared with 79.4% of patients for linezolid. For the second trial, they found that tedizolid met the primary endpoint of ≥ 20% reduction in lesion size at 48 to 72 hours for 85.2% of patients in its group, compared with 82.6% of linezolid patients.
The researchers found safety profiles between the study and comparator drug similar in both studies, with total treatment-emergent adverse events (TEAEs) amounting to 42.7% for tedizolid and 43.2% for linezolid. Nausea, headache, abscess, diarrhea, and vomiting were some of the reported side effects. No death was attributed to the study drug.
Dalbavancin
Dalbavancin is a lipoglycopeptide antibacterial. In its case, two clinical trials for the same conditions compared once-weekly IV dalbavancin with vancomycin/linezolid. The first trial involved 284 patients in each group and the second involved 368 patients in the dalbavancin group and 367 patients in the vancomycin/linezolid group.
Both studies were identical in design. Dalbavancin patients received an IV infusion of 1000 mg on day 1 and a 500 mg IV on day 8. Vancomycin/linezolid patients received 600 mg IV vancomycin doses for at least 3 days with an option to switch to oral linezolid after 3 to 4 days of IV therapy. Dalbavancin patients also were subject to switching to matching placebo if quick improvement and no worsening clinical signs appeared and temperature measurements were positive. Treatment duration lasted for 10 to 14 days.
For the first trial, researchers found that dalbavancin met the primary endpoint of cessation of lesion spread at 48 to 72 hours for 83.3% of its patients compared with 81.8% of vancomycin/linezolid patients. In the second trial, they found that albavancin met the primary endpoint for 76.8% of patients compared with 78.3% of vancomycin/linezolid patients. Key percentages for a secondary endpoint of ≥ 20% reduction in lesion size at 48 to 72 hours were even higher.
Again, researchers found similar safety profiles between dalbavancin and vancomycin/linezolid groups.
Opposition
Two people who spoke at public hearing sessions for both agents, however, questioned the value of the studies both on the basis that they were noninferiority studies comparing drug to drug and not drug to targeted disease, as well as the lack of more comprehensive safety data that could be obtained through more thorough clinical trials.
They also expressed concerns about the lack of diversity among study populations being mostly male and Caucasian, although the committee’s industry representative at the meeting explained that global population studies do not mirror the diversity that would appear in a US-based study.
In explaining their favorable votes committee members expressed support for the studies meeting their primary endpoints, but they also called for language to be inserted in the labeling about postmarket safety monitoring, as well as exclusion of pediatric patients because they represented very few study participants.
The FDA is expected to make a decision on dalbavancin by May 26 and on tedizolid by June 20.
The advisory committee members have disclosed no relevant financial relationships.
http:\\theheart.org
RU
EN