touchRESPIRATORY coverage of ATS 2025:
GREAT-2 was a multi-centre, randomized, double-blind, placebo-controlled trial, investigating the bispecific monoclonal antibody, gremubamab, for the treatment of Pseudomonas aeruginosa infection in patients with bronchiectasis. In this interview, we catch up with Dr Merete Long (University of Dundee, Dundee, UK) around how Pseudomonas aeruginosa infection contributes to disease severity and exacerbation risk in bronchiectasis, and the trial design and findings from the GREAT-2 study.
The abstract “A Bispecific Monoclonal Antibody Targeting Psl and PcrV for Chronic Pseudomonas Aeruginosa Infection in Patients With Bronchiectasis: Results From a Randomized, Double-Blind Placebo-Controlled Trial (GREAT-2).” was presented at ATS 2025 International Conference, San Francisco, 16–21 May.
Questions
- How does Pseudomonas aeruginosa infection contribute to disease severity and exacerbation risk in bronchiectasis? (0:21)
- What was the rationale for investigating gremubamab in bronchiectasis patients with Pseudomonas aeruginosa infection? (1:40)
- Could you give an overview of the trial design and clinical outcomes of the GREAT-2 study? (3:32)
- What were the findings from the study? (4:48)
- What are the broader implications of this trial for future research and clinical practice? (6:49)
Further content in bronchiectasis.
This content has been developed independently by Touch Medical Media for touchRESPIRATORY. It is not affiliated with the American Thoracic Society (ATS). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Editor: Victoria Smith, Senior Content Editor.
Cite: Merete Long. Breaking the Vicious Vortex: Targeting Pseudomonas Aeruginosa Infection in Bronchiectasis – Insights from GREAT-2. touchRESPIRATORY. 2 July 2025.
Abstract: Long MB, Hull RC, Gilmour A, et al. A Bispecific Monoclonal Antibody Targeting Psl and PcrV for Chronic Pseudomonas Aeruginosa Infection in Patients With Bronchiectasis: Results From a Randomized, Double-Blind Placebo-Controlled Trial (GREAT-2). Am J Respir Crit Care Med. 2025;211:A3117.
Disclosures: This short article was prepared by touchRESPIRATORY in collaboration with Merete Long. touchRESPIRATORY utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No fees or funding were associated with its publication.
Transcript
Q1. How does Pseudomonas aeruginosa infection contribute to disease severity and exacerbation risk in bronchiectasis? (0:21)
Along with inflammation, mucociliary dysfunction and lung damage, chronic infection is part of this vicious vortex that describes the complex interplay between factors that actually drive bronchiectasis progression. So the opportunistic pathogen, Pseudomonas aeruginosa, is actually the most common organism causing airway infection in bronchiectasis in both European and US registries and so it’s actually associated with an approximately sevenfold increased risk of hospitalization and a threefold increased risk of mortality. So part of the problem is that it can be resistant to antibiotics, resistant to normal immune clearance mechanisms, and this is partly through its ability to form biofilms. How it contributes to the vicious vortex is namely via a key mechanism, via its release of virulence factors into the airways and into host cells, which can cause things like cell death and cell damage and can promote inflammation. In particular, Pseudomonas infection is associated with neutrophilic inflammation in bronchiectasis, which we know is a significant driver of exacerbations.
Q2. What was the rationale for investigating gremubamab in bronchiectasis patients with Pseudomonas aeruginosa infection? (1:40)
So gremubamab is a bivalent, bispecific monoclonal antibody, and it targets two key proteins on the surface of Pseudomonas aeruginosa and these two key proteins contribute to the bacteria’s persistence and virulence. So the targets are the exopolysaccharide Psl, which is involved in both biofilm formation as well as immune evasion, and also the type III secretion system (T3SS) component PcrV, which Pseudomonas can use to attach to host cells, inject virulence factors, and cause cell damage and inflammation.
So in our initial laboratory study GREAT-1, we actually demonstrated the potential efficacy of gremubamab in the lab. So in this study, we showed that in a global collection of Pseudomonas isolates that were isolated from the airways or airway samples of people with bronchiectasis, these two targets were highly conserved, so at least one of these targets was present in 99% of isolates. We also used primary neutrophils, which were isolated from bronchiectasis patient blood samples, and we showed that gremubamab could actually significantly enhance neutrophil mediated killing of the bacteria. Finally, we also showed that gremubamab could both do things like protect epithelial cells from the cytotoxic effects of Pseudomonas, as well as prevent mortality in a murine infection model. So our initial laboratory study showed the high prevalence of its target’s ability to enhance neutrophil function, as well as to protect the epithelium. These results together indicate gremubamab as a really promising potential therapy to treat Pseudomonas infection in people with bronchiectasis.
Q3. Could you give an overview of the trial design and clinical outcomes of the GREAT-2 study? (3:32)
GREAT-2 was a multicentre, proof-of-concept, phase II trial of the bispecific antibody gremubamab in people with CT-confirmed bronchiectasis and chronic Pseudomonas aeruginosa infection in the UK and in Spain. Patients were randomized equally to one of three trial arms. So this was 1500mg gremubamab, 500mg gremubamab or placebo, and they received this intravenously every 4 weeks for up to 12 weeks. We also included a further 12 weeks off-treatment follow up to understand the longer-term effects. Ultimately, we had 37 participants in our study, so we had 12 in the higher dose arm as well as the placebo group and 13 in the 500mg arm. The primary outcome for the trial was change from baseline in Pseudomonas aeruginosa bacterial load, and this was measured by quantitative cultures at week 12, at the end of the treatment period. Key secondary outcomes included things like change in bacterial load across other study time points, as well as change in patient reported quality-of-life measures, and safety.
Q4. What were the findings from the study? (4:48)
The GREAT-2 trial successfully met its primary endpoint, with the 500mg dose achieving a statistically significant reduction in bacterial load and this was a reduction of around 94% or 1.24 log CFU – so this is similar to the effects shown by antibiotics. We also saw a non-significant trend in the higher dose group towards efficacy as well and reduction, and this was quite promisingly sustained to the end of the trial overall, including three months later at the off-treatment follow-up. Crucially, we also saw a significant and clinically-meaningful improvement in patient-reported quality-of-life measures at the end of the treatment period for both doses, and this is actually far beyond that typically demonstrated with antibiotics and included an almost 11 point reduction for the St. George’s Respiratory Questionnaire (SGRQ) total score for the high-dose group and over 12 points for the lower dose group.
Although our study was relatively small and the time period was relatively short, we also saw a significant prolongation of protocol-defined time-to-first-exacerbation in the higher dose group, with no exacerbation events actually recorded up to week 12 at the end of the treatment period. We know that neutrophilic inflammation can drive exacerbations in bronchiectasis, giving us a really key indication of gremubamab’s mechanism of action in the trial, we actually saw a significant reduction in markers of neutrophilic inflammation in sputum samples from patients. Particularly, this was statistically significant in the high-dose arm, and this included markers like neutrophil granule proteins and so we looked so far at the the azurocidin-1 (Azu-1) and myeloperoxidase (MPO). Finally, regarding evaluation of safety, which was a key endpoint, gremubamab was well tolerated in the trial, with a similar safety profile to the placebo group.
Q5. What are the broader implications of this trial for future research and clinical practice? (6:49)
I think the results of the GREAT-2 trial indicate, firstly, gremubamab is a highly promising therapy for people with bronchiectasis and Pseudomonas aeruginosa infection. These results do now need to be validated in larger clinical trials, but overall this indicates significant promise in potentially reducing our reliance on antibiotic therapies and in helping to break the cycle of chronic infection and inflammation in bronchiectasis. I think that monoclonal antibodies overall represent highly specific therapy, with a reduced risk of off-target effects and resistance compared to conventional antibiotics. So what would be really great is to see this type of therapy developed for other important pathogens, as well as for other diseases in the future.
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