GREAT-2 trial: Gremubamab shows promise in bronchiectasis with chronic Pseudomonas

Q. Why are new treatment approaches needed for Pseudomonas aeruginosa infection in patients with bronchiectasis?

Pseudomonas aeruginosa infection is a very important issue in bronchiectasis, and we have known that for quite some time. It is associated with worse outcomes for patients, including more frequent exacerbations, more hospitalizations, and higher five-year mortality rates. It is also very common, affecting around 25% of patients.

Current European Respiratory Society guidelines recommend long-term antibiotics, but these are not licensed specifically for this indication, largely because previous phase 3 antibiotic trials have produced inconsistent results. Alongside questions around efficacy, antibiotic resistance is also a major concern in this population.

So we really need new treatment approaches, and ideally not another traditional antibiotic, given how many have struggled in the past.

Q. Could you tell us a little about the GREAT-2 trial design and background?

GREAT-2 is a proof-of-concept, double-blind, placebo-controlled phase 2 study conducted in the UK and Spain, with 37 patients recruited across 15 sites.

The trial is evaluating gremubamab, a bispecific monoclonal antibody with two targets. It binds to Psl, which is important in biofilm formation, and PcrV, which plays a key role in the type III secretion system. The rationale is that by targeting both virulence factors, you can cover the majority of clinically relevant strains.

Previous research has shown that around 99% of isolates in bronchiectasis carry PcrV, and about two-thirds carry Psl. That means targeting both should provide broad coverage. Preclinical studies also showed that gremubamab reduced cytotoxicity, improved survival in mouse models, and enhanced immune cell activity against Pseudomonas.

Patients were randomized 1:1:1 to receive 500 mg, 1500 mg, or placebo. Treatment was given intravenously once every four weeks during a 12-week treatment period, followed by a further 12-week follow-up period.

Q. What were the key microbiological findings from the study?

The primary microbiological endpoint was reduction in bacterial load. We found around a 94% reduction in Pseudomonas burden in the 500 mg group at the end of treatment. Importantly, patients continued to show lower levels of Pseudomonas even 12 weeks after treatment had finished.

Using qPCR analysis, we also saw around a 90% reduction in the 1500 mg group, which was not fully captured by culture methods. That was very encouraging.

When we looked at resistance, the isolates appeared remarkably genetically stable over the course of the trial. We did not see the kinds of adaptive mutations that are often associated with antibiotic exposure and emerging resistance. That is very different from what we often see with antibiotics, where bacterial adaptation is common. So overall, it was encouraging evidence that resistance may not be emerging with this approach.

Q. How significant is it that gremubamab binding remained consistent across isolates?

That is another important finding. Even where isolates had deletions affecting one target, gremubamab was still able to bind effectively. This supports the preclinical evidence that only one of the two targets may be needed for successful binding.

That gives us confidence that coverage should remain strong, even if bacteria naturally only have one of the two targets. It suggests this dual-target strategy could remain effective across a wide range of isolates seen in bronchiectasis.

Q. The study also reported positive changes in the microbiome. What could this mean for future management of chronic Pseudomonas infection?

This is probably one of the most exciting aspects of the study. Over the last decade, we have learned that patients with a more balanced respiratory microbiome tend to do better. Higher levels of commensal bacteria are associated with less inflammation, fewer exacerbations, and better overall outcomes.

This is one of the first bronchiectasis trials to show that by targeting a single pathogen, in this case Pseudomonas, you may be able to positively reshape the microbiome. When Pseudomonas levels were reduced, we saw signs of restoration within the microbial community.

That is very different from antibiotics, which tend to affect the whole microbiome, including beneficial organisms. This suggests that highly targeted therapies could allow us to restore balance rather than simply wipe everything out. It also raises the possibility of applying similar approaches to other important pathogens in the future.

Q. What are the next steps for this research?

For GREAT-2, the next major step is the CLEAR trial, which is already ongoing. GREAT-2 was a proof-of-concept study with only 37 patients, so although the findings are very encouraging, they need to be confirmed in a much larger population.

CLEAR is evaluating a next-generation formulation of gremubamab and is recruiting around 425 patients globally. That should give us much stronger data on efficacy, dosing, and which patient groups benefit most.

There is also interest in exploring this approach in other respiratory diseases where Pseudomonas is a major problem, not just bronchiectasis. So there is a lot to look forward to.