2. Academic Validation
  3. 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

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 Med. 2018 Nov;44(11):1787-1796. doi: 10.1007/s00134-018-5229-2.
Bruno François 1 2 3,  Emmanuelle Mercier 4,  Céline Gonzalez 5,  Karim Asehnoune 6,  Saad Nseir 7,  Maud Fiancette 8,  Arnaud Desachy 9,  Gaëtan Plantefève 10,  Ferhat Meziani 11 12,  Paul-André de Lame 13,  Pierre-François Laterre 14,  MASTER 1 study group
Affiliations

Affiliations

  • 1 Service de Réanimation Polyvalente, CHU Dupuytren, 2 Avenue Martin Luther King, 87042, Limoges cedex, France. b.francois@unilim.fr.
  • 2 Inserm CIC1435, CHU Dupuytren, Limoges, France. b.francois@unilim.fr.
  • 3 Inserm, UMR 1092, Faculté de Médecine, Université de Limoges, Limoges, France. b.francois@unilim.fr.
  • 4 Médecine Intensive Réanimation, CHRU de Tours, Tours, France.
  • 5 Service de Réanimation Polyvalente, CHU Dupuytren, 2 Avenue Martin Luther King, 87042, Limoges cedex, France.
  • 6 Réanimation Chirurgicale, CHU, Nantes, France.
  • 7 CHU Lille, Centre de Réanimation, Lille University, Medicine School, Lille, France.
  • 8 Réanimation Polyvalente, CHD Vendée, La Roche-sur-Yon, France.
  • 9 Réanimation et Unité de Soins Continus, CH d'Angoulême, Angoulême, France.
  • 10 Réanimation, CH Victor Dupouy, Argenteuil, France.
  • 11 Faculté de Médecine, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Service de Réanimation, Nouvel Hôpital Civil, Strasbourg, France.
  • 12 Inserm, UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France.
  • 13 Aridis Pharmaceuticals, Inc, San Jose, CA, USA.
  • 14 Service des Soins Intensifs, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
PMID: 30343314 DOI: 10.1007/s00134-018-5229-2
Abstract

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.

Keywords

Adjunctive therapy; HAP/VAP; Monoclonal antibody; Staphylococcus aureus.

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