Bispecific antibody overcomes P. aeruginosa infection in patients with bronchiectasis

The bispecific antibody gremubamab, which targets two proteins on the surface of Pseudomonas aeruginosa, has been shown to substantially reduce bacterial load and improve quality of life for infected bronchiectasis patients in the phase II GREAT-2 study.

The primary endpoint was met, such that at low dose (500 mg), gremubamab yielded a 1.25–log-colony forming unit (CFU) reduction (80 percent confidence interval [CI], –2.33 to –0.16) in bacterial load in sputum samples at the end of treatment at day 84 compared with placebo (1-sided p=0.07099), reported first study author Dr Merete Long from the University of Dundee in Dundee, Scotland, UK. [Long M, et al, ATS 2025]

“This is equivalent to around a 94-percent reduction in bacteria and similar to that seen with some antibiotics,” Long added.

Furthermore, bacterial load reductions achieved with low-dose gremubamab vs placebo persisted even after treatment through day 168 (estimated difference, –1.5, 80 percent CI, –2.44 to –0.56; 1-sided p=0.02).

A similar nonsignificant trend was observed with the high gremubamab dose (1,500-mg) (day 84: estimated difference, –0.66, 80 percent CI, –1.71 to 0.39; 1-sided p=0.2).

Quality of life

“Importantly, we also saw that there was a significant improvement in patient-reported quality of life with both doses of gremubamab,” Long noted.

Total scores on the St. George’s Respiratory Questionnaire (SGRQ) at day 84 decreased by 12.1 points with 500 mg and by 10.8 points with 1,500 mg of gremubamab relative to placebo (p=0.0075 and p=0.0217, respectively), exceeding the minimum clinically important difference of a reduction of 4 points.

Long pointed out that the reduction in SGRQ total scores achieved with gremubamab is not traditionally achieved with antibiotic treatments and suggests that the bispecific antibody could “impact patient lives quite significantly.”

As for other outcomes, with placebo as the comparator, high-dose gremubamab was associated with significantly prolonged protocol-defined time to first exacerbation (estimated difference in restricted mean survival time, 11.4 days; p=0.0457) and reduced sputum markers of neutrophilic inflammation (azurocidin-1: estimated difference, –3.2 log-Azu-1; myeloperoxidase: estimated difference, –0.23 log-MPO; p=0.0305 and p=0.0106, respectively) at day 84.

Long noted that the number of exacerbations throughout the study was low, necessitating cautious interpretation of the time-to-exacerbation data.

Safety

Finally, safety analysis did not show significant differences between gremubamab at either high or low dose and placebo in terms of the percentage of patients who experienced AEs (91.7 percent and 84.6 percent vs 91.7 percent, respectively) or serious AEs (0 percent and 7.7 percent vs 0 percent). The most common AEs deemed “possibly” related to treatment were headache (33.3 percent and 15.4 percent vs 8.3 percent) and nausea (8.3 percent and 15.4 percent vs 0 percent).

AEs led to treatment discontinuation in 25 percent of patients treated with high-dose gremubamab, in 15 percent of those treated with the low dose, and in none of those who received placebo.

Taken together, the results from GREAT-2 “are extremely exciting and really hold promise for the further application of monoclonal antibodies against P. aeruginosa and potentially other pathogens in bronchiectasis,” according to Long.

For GREAT-2, 37 bronchiectasis patients with P. aeruginosa infection were randomly assigned to receive treatment with gremubamab at 1,500 mg (n=12; mean age 65.7 years, 66.7 percent female) or 500 mg (n=13; mean age 60.3 years, 84.6 percent female) or placebo (n=12; mean age 65.9 years, 66.7 percent female). The patients received treatment intravenously every 4 weeks over a 12-week period, with follow-up continuing for another 12 weeks after the final dose.

Next steps for dosing

In a question-and-answer session, Long was asked about the difference in outcomes between the two gremubamab doses—with the lower dose reducing bacterial load more and the higher dose showing greater impact on inflammatory and clinical parameters—and how this would inform the design of the next study, whether the team would go with two doses or with one or the other.

The author responded that drawing definitive conclusions about the efficacy of either dose was challenging due to the limited number of participants in the study. “I don’t think it would be wise to rule either out at this time.”

She pointed out that the observed differences in efficacy between the two gremubamab doses might be partly attributed to the use of colony forming units (CFU) measure in the primary endpoint. “[CFU is] quite variable, and we do see a lot of variability in this parameter across patients, as well as some of those [who received the high dose] having a higher bacterial load at the beginning of the trial.”

“Ultimately, the team would likely be interested in retaining both doses for further investigation,” Long said.