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FDA approves Baxdela for ABSSSIs; more treatments in the pipeline
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The FDA recently approved an IV and oral formulation of Baxdela, an anionic fluoroquinolone, for the treatment of acute bacterial skin and skin structure infections, or ABSSSIs, including MRSA.
The approval of both formulations is supported by data from two phase 3 trials presented at ASM Microbe that showed Baxdela (delafloxacin, Melinta Therapeutics) had similar safety and efficacy profiles against ABSSSIs compared with a combination regimen of vancomycin and aztreonam.
According to David C. Hooper, MD, professor of medicine at Harvard Medical School and chief of the infection control unit and associate chief of the division of infectious diseases at Massachusetts General Hospital, delafloxacin has a wide spectrum of activity against MRSA and other important pathogens, including methicillin-susceptible Staphylococcus aureus and invasive group A Streptococcus.
“It also has gram-negative activity, which can be important in some skin infections, but clearly S. aureus and group A Streptococcus are the dominant pathogens,” Hooper told Infectious Disease News.
The recent approval, he said, has important implications for clinicians treating patients with ABSSSIs, particularly since there are relatively few treatments available with activity against MRSA.
“More companies are bringing new drugs along, which is very important,” Hooper said. “It was pretty lean there for a time and it does look like the pendulum is swinging back in a good direction.”
Delafloxacin effective, well-tolerated
In the two multicenter, double blind, phase 3 trials, researchers randomly assigned 1,510 patients in the United States, Europe, Latin America and Asia in a 1:1 ratio to receive either delafloxacin monotherapy or 15 mg/kg (actual body weight) of vancomycin plus aztreonam for 5 to 14 days. In one trial, patients in the delafloxacin arm received 300 mg IV twice daily. In the other trial, patients in the delafloxacin arm received 300 mg IV twice daily for 3 days and then switched to an oral dose of 450 mg twice daily.
The cohort was diverse, according to Sue Cammarata, MD, chief medical officer of Melinta Therapeutics, and included elderly patients aged older than 65 years (14%) as well as those with obesity (42%), diabetes (11%), renal impairment (16.2%) and history of hepatitis (29%).
“These comorbidities all provide various challenges in antibiotic selection and dosing,” Cammarata told Infectious Disease News.
Of the 438 patients who had a history of hepatitis, the majority (92%) also had a history of substance abuse, which put them at an increased risk for MRSA, Cammarata said.
In the studies, for the patients with history of hepatitis, delafloxacin was noninferior to vancomycin/aztreonam at reducing lesion size at the primary infection site by at least 20% at 48 to 72 hours (86.4% vs. 86.7%). Delafloxacin also had comparable outcomes to vancomycin/aztreonam at a 14-day follow-up visit (83.2% vs. 83%) and a 21- to 28-day follow-up visit (80% vs. 80.3%), and had similar efficacy against MRSA (97.4% vs. 100%).
In a safety analysis, the percentage of patients with at least one treatment-emergent adverse event (AE) was lower in the delafloxacin arm compared with the vancomycin/aztreonam arm (49.5% vs. 60.4%). Aminotransferase increased in four patients who received delafloxacin and in six who received vancomycin/aztreonam. There were no discontinuations among patients who received delafloxacin due to treatment-related AEs. Three patients in the vancomycin/aztreonam arm discontinued treatment due to related AEs.
“There is an advantage to being able to accomplish the same thing with one drug vs. two drugs. You are better off from the side effect standpoint,” Eugene Sun, MD, CEO of Melinta, told Infectious Disease News.
The researchers concluded that delafloxacin appeared to be safe and effective against ABSSSIs in a population with a history of infectious hepatitis and substance abuse.
“We believe that the ability to administer IV and oral Baxdela without the drug monitoring or weight-based dose-adjustments required by standard-of-care antibiotics like vancomycin will be appealing to many doctors,” Cammarata said. “The ability to switch patients from an IV to an oral antibiotic may also resonate with physicians, as it may facilitate hospital discharge, which could have meaningful economic implications.”
Sun anticipates that delafloxacin will be available on the market sometime this fall.
“We are very cognizant of the ecology of correct antibiotic use and we intend to be very adherent to the principles of stewardship,” Sun said. “Baxdela is a very powerful antibiotic, and it is most appropriate for patients with serious infections. However, resistance is an inevitable fact of life, and we think that by using it in a circumspect way, we can keep it at bay as long as possible.”
Additional treatment in the pipeline
Phase 3 data on Taksta (fusidic acid, Cempra) — another oral treatment in the drug pipeline for ABSSSIs, including MRSA — also was presented at ASM Microbe.
Amanda Sheets, PhD, associate director of drug development at Cempra Pharmaceuticals, which conducted the study, characterized the results as “pivotal” to finally getting fusidic acid approved in the U.S.
Partly due to legislative hurdles, fusidic acid has remained an investigational agent in the U.S., despite being in use globally since the 1960s. According to Sheets, because the antibiotic has never been marketed in the U.S., it is unlikely that there would be much resistance to the agent among staphylococci. Indeed, she said monitoring of bacterial isolates from the U.S. over the past 6 years has shown only rare resistance in MRSA and methicillin-sensitive Staphylococcus aureus.
Sheets said the strong activity of fusidic acid against MRSA infections demonstrated in the phase 3 study “would provide physicians with an important new option in their armamentarium.”
“Considering complicated skin infections are one of the most rapidly growing reasons for hospitalizations and emergency department visits each year, the results with [fusidic acid] in this study are promising, especially for an outpatient population where there is a need for new oral drugs that are effective against MRSA,” she told Infectious Disease News.
Sheets and colleagues enrolled 716 patients with cellulitis (26%), wound infection (61%) or major cutaneous abscess (13%) from 62 sites in the U.S. and randomly assigned them to receive a 10-day course of either oral fusidic acid or oral Zyvox (linezolid, Pfizer). Approximately 65% of the patients were male and the mean age was 45 years.
Most — 68% — of the infections treated during the trial were associated with IV drug use, Sheets and colleagues reported. Almost 60% of the patients were diagnosed with an S. aureus infection, including 235 cases of MRSA. The next most common pathogens were S. anginosus group species and S. pyogenes.
The primary endpoint was early clinical response (ECR) — a 20% or greater reduction in lesion size after 48 to 72 hours without receipt of rescue antibiotics — in the intent to treat (ITT) population.
According to Sheets and colleagues, ECR was recorded in 87.2% of patients who received fusidic acid compared with 86.6% in the linezolid arm. Additionally, fusidic acid showed comparable efficacy to linezolid at the end of therapy (91.9% vs. 89.6%) and at post-therapy evaluations after another 7 to 14 days (88.6% vs. 88.5%).
Fusidic acid was 100% effective in end-of-therapy (EOT) and post-therapy evaluations (PTE) among the 99 microbiologically evaluable patients with MRSA. For microbiologically evaluable patients with MRSA who received linezolid, the drug was effective in 98.1% at EOT and 96.2% at PTE. Treatment-related adverse events occurred in 37.9% of patients who received fusidic acid compared with 36.1% of patients in the linezolid arm, with gastrointestinal events being most common.
Fusidic acid landed on a list of “old” antibiotics under the FDA Modernization Act (FDAMA), which made it ineligible for market exclusivity — one of the reasons it remains an investigational drug in the U.S., Sheets said. The antibiotic was a generic drug by the time the FDAMA was passed in 1997, and it is unclear why pharmaceutical companies did not attempt to bring it to the U.S. in the decades leading up to the legislation, according to Sheets.
The landscape in the U.S. has changed in more recent years, potentially opening the door to fusidic acid’s use. According to Sheets, the FDAMA was amended in 2008 to allow “old” antibiotics like fusidic acid that were never approved in the U.S. to benefit from regulatory market exclusivity upon approval.
“Since [fusidic acid] was a generic drug, no company had been willing to make the investment in its development for the U.S. market, lacking both [intellectual property protection] for the drug and regulatory market exclusivity,” she explained.
After Cempra demonstrated that a loading dose regimen of fusidic acid reduced the likelihood that target bacteria would develop resistance to it, a patent was issued to provide intellectual property protection to fusidic acid use in the U.S., according to Sheets.
Sheets said efforts by Congress and the FDA to incentivize antibiotic development have further set the stage for Cempra to invest in getting fusidic acid approved. She said Cempra expects that a second successful phase 3 trial would be needed before it submits a New Drug Application to the FDA. – by Stephanie Viguers and Gerard Gallagher
- References:
- Cammarata S, et al. Delafloxacin (DLX) is Effective and Well-Tolerated Compared to Vancomyin/Aztreonam (VAN/AZ) in Treatment of Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and History of Infectious Hepatitis.
- Sheets A, et al. Results of a phase 3 trial comparing oral sodium fusidate (fusidic acid) versus oral linezolid for treatment of acute bacterial skin and skin structure infections (ABSSSI).
Disclosures: Cammarata is an employee of Melinta Therapeutics. Sheets is employed by Cempra. Hooper reports serving on the delafloxacin advisory board for Melinta. Sun is CEO of Melinta.