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

Francois, Bruno;Mercier, Emmanuelle;Asehnoune, Karim;Nseir, Saadalla;Laterre, Pierre-François;et.al.
(2018) Intensive Care Medicine — Vol. 44, n° 11, p. 1787-1796 (2018)

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  • Francois, Bruno
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  • Mercier, Emmanuelle
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  • Asehnoune, Karim
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  • Nseir, Saadalla
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  • Laterre, Pierre-FrançoisUCLouvain
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Abstract
(en) PURPOSE: 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 follow-up 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.
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Francois, B., Mercier, E., Asehnoune, K., Nseir, S., Fiancette, M., Gonzalez, C., Barraud, O., De Lame, P.-A., & Laterre, P.-F. (2018). 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. Intensive Care Medicine, 44(11), 1787-1796. https://doi.org/10.1007/s00134-018-5229-2 (Original work published 2018)