suvratoxumab (MEDI4893) / AstraZeneca, Aridis - LARVOL DELTA

Exploring Human Use of Monoclonal Antibodies Against Critical Bacteria: A Scoping Review of Clinical Trials. (PubMed, Infect Dis Ther) - "Inconsistent efficacy may stem from complex host-pathogen interactions, biofilm formation, and variations in patient immune status. Future trials should investigate early mAb administration, stratified patient selection, and standardized antibiotic coadministration, poorly addressed thus far. Optimized dosing and mAb combination regimens are promising yet unexplored paths, while high production costs and regulatory issues remain a significant barrier."

Journal • Review • Infectious Disease • Pneumonia • Respiratory Diseases

Structure of ClfA002 in complex with neutralizing antibody AZD7745 provides insight into its broad neutralization mechanism in Staphylococcus aureus infection. (PubMed, J Infect Dis) - "ClfA is ubiquitously present on S. aureus global clinical isolates, and AZD7745 epitope is highly conserved. This suggests that AZD7745 can confer broad coverage against S. aureus."

Journal • Infectious Disease

SAATELLITE-2: A Human Monoclonal Antibody Against Staphylococcus Aureus Alpha Toxin in Mechanically Ventilated Adult Subjects - 2 (clinicaltrials.gov) - P3 | N=24 | Terminated | Sponsor: Aridis Pharmaceuticals, Inc. | N=564 ➔ 24 | Recruiting ➔ Terminated | Trial primary completion date: Oct 2023 ➔ Jul 2024; The study was terminated due to administrative reasons

Enrollment change • Trial primary completion date • Trial termination • Infectious Disease • Pneumonia • Respiratory Diseases

The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches. (PubMed, Cell Rep Med) - "In passive immunization platforms, natural anti-SA human antibodies reduce the efficacy of the human monoclonal antibodies suvratoxumab and tefibazumab, consistent with the results of their respective clinical trials. Strikingly, in the absence of specific humoral memory responses, active immunizations are efficacious in both naive and SA-experienced mice. Overall, our study points to a practical and predictive approach to evaluate and develop SA vaccines based on pre-existing humoral imprint characteristics."

Journal

SAATELLITE-2: A Human Monoclonal Antibody Against Staphylococcus Aureus Alpha Toxin in Mechanically Ventilated Adult Subjects - 2 (clinicaltrials.gov) - P3 | N=564 | Recruiting | Sponsor: Aridis Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Pneumonia • Respiratory Diseases

Performance of the Cepheid Methicillin-Resistant Staphylococcus aureus/S. aureus Skin and Soft Tissue Infection PCR Assay on Respiratory Samples from Mechanically Ventilated Patients for S. aureus Screening during the Phase 2 Double-Blind SAATELLITE Study. (PubMed, J Clin Microbiol) - "The qPCR assay was easy to perform, sensitive, and standardized and provided better sensitivity than conventional culture for S. aureus detection. Quantitative PCR C output correlated with suvratoxumab efficacy in reducing S. aureus pneumonia incidence or death in S. aureus-colonized, mechanically ventilated patients."

Journal • P2 data • Infectious Disease • Pneumonia • Respiratory Diseases

A study to see if suvratoxumab is safe and works to stop pneumonia developing in people who are on mechanical ventilators who have a bacteria in their lungs, commonly called Staphylococcus, that has not yet caused an infection. (clinicaltrialsregister.eu) - P3 | N=564 | Sponsor: Aridis Pharmaceuticals, Inc.

New P3 trial • Dermatology • Infectious Disease • Pneumonia • Respiratory Diseases

SAATELLITE-2: A Human Monoclonal Antibody Against Staphylococcus Aureus Alpha Toxin in Mechanically Ventilated Adult Subjects - 2 (clinicaltrials.gov) - P3 | N=564 | Not yet recruiting | Sponsor: Aridis Pharmaceuticals, Inc.

New P3 trial • Infectious Disease • Pneumonia • Respiratory Diseases

"This #SundayScience read the SAATELLITE #publication on the efficacy & safety of suvratoxumab for prevention of #Saureus Ventilator-Associated #pneumonia was released in @TheLancetInfDis ➡️ https://t.co/8YWdqcNapT @IMI_JU @EFPIA @CHULimoges @ESCMID @AstraZeneca" (@COMBACTE)

Clinical • Infectious Disease • Pneumonia • Respiratory Diseases

"#TwitteRx #IDTwitter ⤵️ #suvratoxumab" (@mmPharmD)

Efficacy and safety of suvratoxumab for prevention of Staphylococcus aureus ventilator-associated pneumonia (SAATELLITE): a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial. (PubMed, Lancet Infect Dis) - P2 | "In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies."

Clinical • Journal • P2 data • Critical care • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Phylogenetic and alpha toxin variant analyses of Staphylococcus aureus strains isolated from patients during the SAATELLITE study (IDWeek 2020) - P2 | "Our data indicated that: 1) suvratoxumab target region in (AT) remains conserved; 2) suvratoxumab is active against all AT variants identified to date; 3) suvratoxumab did not exert pressure on SA clinical isolates for selection of escape mutants."

Clinical • Infectious Disease

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment. (PubMed, JCI Insight) - "FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection."

Journal • Immunology • Infectious Disease • Pneumonia • Respiratory Diseases

Efficacy and Safety Profile of Suvratoxumab, a Novel Anti-Staphylococcus aureus Monoclonal Antibody: Results of the SAATELLITE Study in Mechanically Ventilated Intensive Care Unit Patients (ECCMID 2019) - P2 | "A single intravenous suvratoxumab dose produced a trend toward reduced incidence of SA pneumonia and reduced HRU in high-risk ICU patients. Suvratoxumab also demonstrated acceptable safety, PK, and ADA profiles. These results support continued development of suvratoxumab in MV ICU patients."

Clinical • Infectious Disease • Pneumonia • Respiratory Diseases

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice. (PubMed, J Clin Invest) - "Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival...Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival."

Journal • Preclinical

Candida albicans Augments Staphylococcus aureus Virulence by Engaging the Staphylococcal agr Quorum Sensing System. (PubMed, mBio) - "Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody...Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host."

Journal

Alanine scanning mutagenesis of the MEDI4839 (Suvratoxumab) epitope reduces alpha toxin lytic activity in vitro and S. aureus fitness in infection models. (PubMed, Antimicrob Agents Chemother) - "MEDI4893 effectively neutralized all the lytic mutants in vitro and in vivo When the defective mutants were introduced into a S. aureus clinical isolate, the mutant-expressing strains exhibited less severe disease in mouse models and were effectively neutralized by MEDI4893. These results indicate the MEDI4893 epitope is highly conserved due, in part to its role in AT pore-formation and bacterial fitness, thus decreasing the likelihood for the emergence of mAb-resistant variants."

Journal • Preclinical

Performance of the Cepheid Rapid PCR Test for Patient Screening and Association with Efficacy of Suvratoxumab, a Novel Anti-Staphylococcus aureus Monoclonal Antibody, During the Phase 2 SAATELLITE study (IDWeek 2019) - P2; "In subjects with low SA load (Ct≥29; n=72), suvratoxumab provided 66.7% RRR [90% confidence interval (CI): 21.3%, 86.2%] compared to 31.9% RRR [90% CI: -7.5%, 56.8%] in total study population.Conclusion : Cepheid Xpert PCR assay was easy to perform, sensitive and standardized, and provided better sensitivity than conventional culture for detection of SA. Additionally, quantitative PCR Ct output was associated with efficacy of suvratoxumab in reducing SA pneumonia incidence."

Clinical • P2 data

Population Pharmacokinetics of Suvratoxumab (MEDI4893), An Extended Half-life Staphylococcus aureus Alpha Toxin-neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units. (IDWeek 2019) - P2; "Conclusion : MV status, post-dose duration on MV, bodyweight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients."

Clinical • PK/PD data

Efficacy, Pharmacokinetics (PK), and Safety Profile of Suvratoxumab (MEDI4893), a Staphylococcus aureus Alpha Toxin (AT)-Neutralizing Human Monoclonal Antibody in Mechanically Ventilated Patients in Intensive Care Units; Results of the Phase 2 SAATELLITE Study Conducted by the Public-Private COMBACTE Consortium. (IDWeek 2019) - P2; "Conclusion : A single intravenous dose of suvra produced a trend toward reduced incidence of SA pneumonia, health resource savings, sustained functional exposure in serum, and an acceptable safety profile. These results support continued development of suvra in MV ICU patients."

Clinical • P2 data • PK/PD data

Suvratoxumab Reduces Staphylococcus Aureus Pneumonia in High-Risk ICU Patients: Results of the SAATELLITE Study (ATS 2019) - P2; "A single intravenous dose of suvratoxumab resulted in a trend toward lower incidence of SA pneumonia and a favorable safety profile in SA-colonized and mechanically ventilated ICU patients. Study results support continued clinical development of suvratoxumab in this patient population."

Clinical • Late-breaking abstract