October 4, 2012 (San Francisco, California) — A phase 2 trial has found brilacidin, a new drug in a novel class of antibiotics, to be effective and safe for acute bacterial skin and skin structure infections (ABSSSI) caused by Staphylococcus aureus.
Daniel Jorgensen, MD, MPH, MBA, an infectious disease physician and senior vice president and chief medical officer of PolyMedix in Radnor, Pennsylvania, reported the results in a poster session here at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy.
In this double-blind active-comparator study conducted at 21 sites in Canada, Russia, and Ukraine, 215 patients with ABSSSI and evidence of methicillin-sensitive or methicillin-resistant S aureus were randomized to receive daptomycin for 7 days or 1 of 3 doses of brilacidin: an intravenous (IV) loading dose on day 1 of 0.40 mg/kg (low-dose group), 0.75 mg/kg (medium-dose group), or 1.0 mg/kg (high-dose group), followed by 4 days of IV brilacidin at 0.30 to 0.35 mg/kg and then 2 days of placebo.
The researchers performed efficacy and safety assessments during treatment (day 2/3), at the end of treatment (day 7/8), as a test of cure (days 10 to 14), and on long-term follow-up (day 28). Serial photographs of skin lesions were reviewed by trained infectious disease physicians to confirm the evaluations at all time points.
Effective at All Doses
Efficacy, whether defined by the criteria of the US Food and Drug Administration (FDA) or the trial sponsor, was very good, according to the researchers. The FDA criteria included cessation of spread of erythema, edema, and induration; no increase in lesion size; and the absence of fever. Sponsor-defined criteria included a decrease in lesion size and signs and symptoms, and no additional surgery to treat the infection after day 1. Both sets of criteria included no additional antibacterial drugs (although the cut-off time for their use was different).
Using the sponsor's definition, clinical response rates ranged from 91.4% to 97.5% on day 2/3, and from 80.0% to 97.4% on day 28 in the 3 brilacidin groups. For daptomycin, the clinical response rate was 91.5% on day 2/3 and 93.6% on day 28.
Sponsor-Defined Clinical Response Rates in the Brilacidin and Daptomycin Groups
|Time of Assessment|| Low-Dose Brilacidin, %
(n = 40)
| Medium-Dose Brilacidin, %
(n = 35)
| High-Dose Brilacidin, %
(n = 39)
| Daptomycin, %
(n = 47)
Dr. Jorgensen explained that the 95% confidence intervals for the clinical response rates of the brilacidin and daptomycin groups overlapped. "That gives us a lot of flexibility in terms of bringing [the brilacidin] dose down and shortening the course of therapy, maximizing efficacy and minimizing any adverse events," he told Medscape Medical News.
Graphs of time to complete clinical response and time to fever resolution showed essentially overlapping lines for all 3 doses of brilacidin and for daptomycin. Complete clinical responses began on day 4 and continued to rise until day 28. Time to fever resolution began on day 1 and peaked at greater than 90% by day 4/5.
The most common treatment-related adverse events with brilacidin were numbness and tingling (including paresthesias and similar sensory disturbances), with 65% of patients in the low- and medium-dose groups and 87% of those in the high-dose group affected.
The researchers describe the events as transient and mild, and indicated that they did not lead to any discontinuations. Only 1 of 55 patients (1.8%) in the daptomycin group experienced numbness and tingling. Excluding numbness and tingling, treatment-related adverse events occurred in 5.6% to 9.6% of patients in the brilacidin groups and in 10.9% of those in the daptomycin group.
In the brilacidin groups, 1.9% of patients in the low-dose group, 3.7% in the medium-dose group, and 5.6% in the high-dose group experienced elevated systolic blood pressure. In the daptomycin group, no patients did. The elevated blood pressures resolved in less than 24 hours. Geographic clustering of patients with elevated blood pressure at 2 sites has prompted the researchers to evaluate possible methodological errors.
Fifteen patients discontinued brilacidin because of a treatment-related serious or other adverse events. There were no discontinuations in the daptomycin group.
There was no evidence of liver or kidney toxicity, no deaths, and no prolongation in the QTc interval with brilacidin, Dr. Jorgensen said.
The researchers conclude that 5 days of brilacidin administered at any of the doses is safe and produces early and sustained clinical response rates equivalent to those seen with daptomycin in the treatment of ABSSSI.
Future studies will explore lower doses and shorter courses of brilacidin. "It has a longer half-life than most antibiotics [16 to 22 hours], and it has what we call a postantibiotic effect," Dr. Jorgensen noted. Because of its pharmacokinetic and pharmacodynamic properties, it might be possible to front-load the dose and shorten treatment, he explained.
Brilacidin is one of a series of small-molecule defensin mimetics that PolyMedix is developing. "Basically, it's a synthetic mimic of our body's own host defense proteins," Dr. Jorgensen told Medscape Medical News. Protein-based defensin mimetics have been tried previously, but they are difficult to develop. He said this compound is the first involving a nonpeptide small molecule. Beyond its antibiotic properties, brilacidin has antiinflammatory and antibiofilm properties, Dr. Jorgensen said.
After viewing the poster, Jesús Rodríguez-Baño, MD, PhD, professor and head of infectious diseases at the Hospital Universitario Virgen Macarena and the University of Seville in Spain, told Medscape Medical News that brilacidin is "not only a new drug, it also has a new mechanism of action."
He said that skin and soft tissue infections "are the easy infections for all drugs.... It would be very attractive to see if it works in other types of infections, not only skin and soft tissue."
Dr. Rodríguez-Baño cautioned that data from phase 3 trials are needed, "but this is a very, very interesting start for a new era in antibiotic therapy."
This trial was sponsored by PolyMedix. Dr. Jorgensen is an employee of PolyMedix. Dr. Rodríguez-Baño has disclosed no relevant financial relationships.
52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract L1-1662. Presented September 11, 2012.
Medscape Medical News © 2012 WebMD, LLC
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