Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused by Staphylococcus aureus: first-in-human trial

Abstract

Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics.Methods: Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative followup culture and presumed to be negative when no culture was obtained in the presence of clinical improvement.Results: Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days.Conclusions: Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…AR-301 was administered via intravenous infusion over two hours, starting within 36 h of the diagnosis of severe pneumonia. The pharmacokinetic profile of AR-301 is consistent to that of a human IgG1 monoclonal antibody, with a half-life of approximately 25 days [232]. AR-301 (22 patients (71%)) was not statistically different compared to placebo (14 patients (87.5%)) in terms of rate of clinical cure on Day 28 [232].…”

“…AR-301 (trade name Salvecin), developed by Aridis Pharmaceuticals, is a fully human monoclonal antibody that specifically neutralises alpha toxins, produced by S. aureus [232,233]. Alpha-toxin is a key virulence factor of S. aureus and can lead to tissue disruption, bacterial dissemination, immune dysregulation and programmed cell death when released into the infected host cell [234,235].…”

“…Alpha-toxin is a key virulence factor of S. aureus and can lead to tissue disruption, bacterial dissemination, immune dysregulation and programmed cell death when released into the infected host cell [234,235]. Alpha toxin has also recently been shown to modulate the activity of macrophages in co-infecting pathogens, including P. aeruginosa and Klebsiella pneumoniae [232]. Therefore, the neutralisation of alpha toxins should prevent damage caused by the toxin and bacteraemia [236].…”

“…Therefore, the neutralisation of alpha toxins should prevent damage caused by the toxin and bacteraemia [236]. Unpublished data have shown AR-301 to be protective both prophylactically and therapeutically against S. aureus [232].…”

“…A first-in-human, single-ascending dose, phase I/IIa study was conducted to investigate the safety and tolerability of AR-301 as an adjunctive therapeutic treatment to standard antibiotics in 48 patients with severe S. aureus pneumonia (NCT01589185) [232]. AR-301 was administered via intravenous infusion over two hours, starting within 36 h of the diagnosis of severe pneumonia.…”