Trial Confirms Efficacy, Safety Of Intravenous Iclaprim As Skin Infection Treatment
Arpida (SWX: ARPN) today presented the combined results from two pivotal Phase III clinical trials at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th annual meeting in Washington, DC.
In these studies, intravenous iclaprim, a novel antibiotic, showed high clinical cure rates which were similar to those of the comparator drug, linezolid, in the treatment of complicated skin and skin structure infections (cSSSI) caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In addition, iclaprim was well-tolerated with a safety profile that compared favorably to linezolid. A New Drug Application for intravenous iclaprim in cSSSI will be discussed at the meeting of the U.S. Food and Drug Administration Anti-Infective Drugs Advisory Committee on 20 November 2008.
Iclaprim, a novel antibiotic from the trusted dihydrofolate reductase (DHFR) selective inhibitor class of antibiotics, was specifically designed to address the growing need for additional treatment options to combat resistant infections including MRSA. MRSA affects more than 2 million people in the United States each year and rates of hospital- and community-acquired MRSA are on the rise.(i,ii)
"The high efficacy rates and favorable tolerability profile of iclaprim strongly supports its potential as a new treatment option for patients who have acquired serious infections caused by MRSA," said Dennis L. Stevens, MD, PhD, Veterans Affairs Medical Center, Boise, Idaho. "With rates of MRSA increasing and effectiveness of some current antibiotics declining, it is important to identify effective alternative treatments for these infections."
The results presented at the ICAAC/IDSA meeting were gathered from the ASSIST-1 and ASSIST-2, (Arpida's Skin and Skin Structure Infection STudy) pivotal Phase III studies involving a total of 991 patients. In a combined efficacy analysis, the clinical cure rate at the test-of-cure visit was 82.2 percent for iclaprim versus 85.3 percent for linezolid in the intent-to-treat population and cure rates were 92.3 percent and 97.8 percent, respectively, in the per protocol population. Data from the studies also show that iclaprim exhibited a high eradication rate for MRSA (76.4 percent), which was comparable to that of linezolid (78.7 percent).
Overall, iclaprim was found to be safe and well-tolerated at a dose of 0.8 mg/kg in the Phase III ASSIST trials. Adverse events were found to be less frequent among patients treated with iclaprim as compared to linezolid. In earlier Phase I trials, iclaprim was shown to have a low propensity for interactions with other drugs.
"These data further support the safety and efficacy of iclaprim as a potential treatment against complicated skin and skin structure infections," said Jurgen Raths MD, President and CEO of Arpida. "Arpida remains encouraged and optimistic about the potential of iclaprim for the treatment of MRSA and related infections, and looks forward to bringing iclaprim to market, providing a new treatment option for physicians."
The ASSIST Trials
The ASSIST trials were randomized, multi-center, double-blind, Phase III studies designed to establish the efficacy and safety of iclaprim in the treatment of patients with cSSSI known or suspected to be caused by Gram- positive pathogens. The trials were of essentially identical design, making a combined analysis of iclaprim possible in a larger population. A 95 percent confidence interval was used to determine statistical significance of study data and the pre-specified non-inferiority margin (-12.5 percent) was met in all populations in both trials.
A total of 991 patients, 18 years old and over with cSSSIs were enrolled in the trials. Patients were treated for 10 to 14 days with either 0.8 mg/kg iclaprim or 600 mg linezolid, both administered intravenously twice daily and analyzed based on populations, including intent-to-treat (ITT), modified intent-to-treat (MITT), per protocol (PP) and modified clinical evaluable (MCE).
-- The ITT population included all patients who received at least one dose of medication;
-- The MITT population included all patients in the ITT population who had an infecting Gram-positive pathogen isolated at baseline;
-- The PP population excludes all patients with any protocol violation; and
-- The MCE population was the same as the PP population, but adding back clinically evaluable patients whose protocol violation was use of additional systemic or topical prohibited antibiotics or high-dose steroids registered as clinical failures.
The causative pathogen distribution in the study population was well-balanced between treatment groups with Staphylococcus aureus (S. aureus) as the predominant pathogen isolated at baseline (76.5 percent for iclaprim and 81.1 percent for linezolid), of which 40 percent of isolates were MRSA.
Patients were evaluated daily for the first four days and then every other day thereafter during the treatment period, at the end of therapy, at the test-of-cure (TOC) visit (7 to 14 days post treatment) and at a late follow-up visit 7 to 14 days after the TOC visit. The primary endpoint was the comparative clinical cure rates of iclaprim and linezolid at the TOC visit in the ITT and PP populations.
The most commonly reported adverse events in the clinical studies were: gastrointestinal disorders (7.4 percent versus 10.4 percent for iclaprim and linezolid, respectively); general disorders and administration site conditions (4.2 percent versus 3.9 percent); nervous system disorders (4.8 percent versus 6.5 percent); and skin and subcutaneous tissue disorders (4.2 percent versus 4.5 percent).