So the first clinical trial in patients with bronchiectis with renzakib was the Willow trial, which randomized 256 patients to either 25 mg of renzacateib, 10 mg of renzacateib or placebo for 6 months with a primary outcome of the time to first exacerbation. The doses of renzacateib were selected based on phase one studies in healthy volunteers that showed that both of those doses. Achieved clinically relevant reductions in the levels of active neutrophil serum proteases, and with an acceptable safety profile, and so that led on to the, the phase two study in people with bronchiectasis. The studies enrolled patients with 2 or more exacerbations per year who had CT confirmed bronchiectasis. Patients had multiple causes of bronchiectis, but patients with a primary diagnosis of COPD or asthma were excluded, as were some other causes such as cystic fibrosis. The, the trial was, uh, incredibly exciting in terms of its outcome because, uh, both the 10 mg and the 25 mg dose significantly prolonged the time to first exacerbation, compared with placebo, so it was a highly positive study with approximately a 40%. Reduction in the risk of exacerbation for both doses, it was really interesting that there was no difference between the 10 mg and the 25 mg in terms of efficacy on the exacerbation endpoint, um, and at the time that was, that was surprising because the 25 mg did have a larger effect on the biomarkers, on the, the reductions in sputum neutrophil elastase. There were also encouraging results on the frequency of exacerbation, uh, and also, although not statistically significant because the study wasn't powered, um, trends suggesting the potential preservation of lung function with renzakib compared with placebo, and that becomes important when I will tell you about the phase 3 trial. Um, additional exploratory analysis of what was happening in the Willow trial using biological samples taken during the study, uh, showed reductions in airway mucus, which is obviously a major driver of symptoms and, and gave us encouragement that we may be able to see even more positive data in, in larger trials going forward. Something that was remarkable in the Willow study was that the consistency of effect across different subgroups was really striking. Bronchiex is a very heterogeneous disease, and so you expect that drugs, treatments will work differently in different subgroups of patients based on cause or severity, lung function, bacterial pathogen, but remarkably renzicib seemed to provide a similar reduction in exacerbations across all of these groups, uh, which, To me it makes sense because the neutrophil is so central to all of these things. The way I think about bronchiectasis is it is, it's caused by lots of different things, there are lots of different factors, but they all pass through the same central train station, which is the, the neutrophilic inflammation, that's the central feature that all of these patients have, and the Willow study really pointed towards that being, being the case. The other thing that was incredibly important in Willow was the safety data. So Papillon LeFevre syndrome, a rare genetic condition caused by absence of DPP1, has two main manifestations, uh, thickening of the hands and, and feet, what we call hyperkeratosis, uh, and periodontitis, inflammation, uh, dental issues, uh, both of which were looked for really carefully in the Willow study. Although there was a small increase in hyperkeratosis, particularly at the 25 mg dose, uh, these events were mild and not something that caused significant, uh, difficulties for patients, and so it was seen as a manageable side effect. In addition, in Willow, patients visited the dentist regularly so that we could really carefully monitor whether there's any uh onset or progression of periodontitis during the study. And here, although there was a small increase in the reporting of dental adverse effects in people receiving renzakaib, detailed dental examination with things like pocket depth, uh, measurements. showed no significant dental adverse issues uh caused by renzicib, no progression of periodontitis caused by renzicib. So both, those aspects of safety were very reassuring, as well as the fact that we saw no increased risk of severe infections, which is always a concern with uh any drug that's targeting the neutrophil. So the Willow study was really a landmark. I still remember where I was and what I was doing when we, when we got those results and just how exciting it was, uh, to realize we had an effective anti-inflammatory therapy that reduced the risk of exacerbation, and that the safety profile was really very reassuring, laying the foundation for then larger studies, uh, to take forward that approach to care for people with bronchiectasis.
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