Iclaprim Non-Inferior to Vancomycin in Treating Patients with Wound Infections

Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor, being developed for the treatment for wound infections linked with gram-positive pathogens, has previously shown to be well tolerated in the REVIVE trials. But new data pooled from both trials found iclaprim to be non-inferior to vancomycin in the treatment of wound infections.

In a poster abstract presentation at ID Week 2018 in San Francisco, California, David Huang, MD, PhD, chief medical officer of Motif Bio, presented the efficacy and safety data from a pooled analysis from the 2 phase 3 trials, REVIVE-1 and REVIVE-2 evaluating iclaprim in comparison to vancomycin.

“Iclaprim is an antibiotic from an underutilized mechanism of action (trimethoprim is the only US Food and Drug Administration (FDA)-approved dihydrofolate reductase inhibitor); is rapidly bactericidal against nonsusceptible Methicillin-resistant Staphylococcus aureus (MRSA) isolates/strains to vancomycin, linezolid, and daptomycin; suppresses bacterial exotoxin production; and is not nephrotoxic and thus does not require renal dose adjustment,” Dr. Huang said in an interview with Contagion®.

The purpose of the REVIVE trials was to conduct double-blind, randomized, active-controlled, multinational, multicenter trials to compare the efficacy of iclaprim administered as an 80-mg fixed dose when compared with 15 mg/kg of vancomycin in patients with acute bacterial skin and skin structure infections, including surgical site infections. Both drugs were administered intravenously over 2 hours, every 12 hours for 5 to 14 days, depending on the investigator assessment of clinical response.

The primary endpoint of the REVIVE studies was to determine whether iclaprim was non-inferior (10% margin) at 48 to 72 hours after the initiation of the study drug compared with baseline in the intent-to-treat population.

A total of 50% (602/1198) of the patients in the 2 studies were treated for wound infections, 51% were treated with iclaprim and 49% were treated with vancomycin. Similar baseline characteristics and demographics were observed in both treatment arms of the pooled REVIVE studies, with the exception of fewer diabetics and more illicit drug users in the iclaprim arm.

Microbiological findings at baseline for patients with wound infections, indicate that in the pooled analysis, 72% of patients in both the vancomycin and iclaprim treatment arms with available isolates from wound infections had S aureus. Additionally, in both treatment arms, MRSA accounted for approximately 50% of S aureus isolates in wound infections.

The investigators observed that iclaprim had similar early clinical response rates at an early time point compared with vancomycin among the subset of patients with wound infections. [(83.2% vs 78.2%) Treatment difference of 5.01% (95% Confidence Interval [CI]: -1.29, 11.32)]. The median treatment duration for both iclaprim and vancomycin was 7 days (range 5-14 days). Additionally, clinical cure at test-of-cure were similar (85% and 84% in the iclaprim and vancomycin arms, respectively).

Iclaprim and vancomycin had similar adverse event profiles in patients with wound infections. Two patients treated with vancomycin had serum creatinine levels 3 or more times the upper limit of normal, which was not observed in the iclaprim trial.

In the post-hoc analysis, iclaprim achieved non-inferiority to vancomycin in both studies in the subgroup of patients with wound infections.

“Iclaprim was shown to be non-inferior to vancomycin for an early clinical response among patients with ABSSSI in the REVIVE Trials…” Dr. Huang explained to Contagion®. “No significant differences between arms in elevated liver enzymes or QTc prolongation. Also, [there were] no reported cases of Clostridium difficile.”

The rolling New Drug Application submission for iclaprim was completed in June and a Prescription Drug User Fee Act (PDUFA) date has been set for February 13, 2019. According to Dr. Huang, Motif Bio is also preparing to submit a Marketing Authorization Application by the end of 2018.