Good afternoon, and welcome to the Insmed Post ATS Investor Call to review brinzocafib Willow data and Program Review. All participants will be in listen only mode. Please note this event is being recorded. I would now like to turn the conference over to Sarah Bondstein. Please go ahead.
Thank you. Good afternoon, and welcome to today's conference call to discuss new data from our Phase 2 WILLOW study of brentocatid in non cystic fibrosis bronchiectasis presented earlier today at the American Thoracic Society virtual meeting. Before we start, let me remind you that today's call will include forward looking statements based on current expectations. Such statements represent our judgment as of today and may involve risks and uncertainties that may cause actual results to differ materially from the results discussed in the forward looking statements. Please refer to our filings with the SEC, which are available through the SEC's website atwww.sec.gov or from our website for information concerning the risk factors that could affect the company.
Joining me on today's call are members of the Insmed executive management team, including Will Lewis, Chairman and Chief Executive Officer Roger Adsett, Chief Operating Officer and Doctor. Martina Flammer, Chief Medical Officer. I'm also pleased to welcome James Chalmers, Professor and Consultant Respiratory Physician at the School of Medicine, University of Dundee, UK, who will walk us through the new data shared earlier today. Let me now turn the call over to Will Lewis for opening remarks. Will?
Thank you, Sarah. Good afternoon, everyone, and thank you for joining us. We hope you and your families remain safe and healthy during these challenging times. Let me start by thanking Professor James Chalmers for his efforts as the lead investigator for the Phase 2 WILLOW study of brincocatsib in patients with non CF bronchiectasis. We are very excited about the positive study results and what they mean for patients with this disease.
James will walk you through those results shortly. I'd also like to thank the American Thoracic Society for allowing us to broadly share these data. The detailed study results you'll see today certainly reinforce our view that brenzocatib holds meaningful promise in bronchiectasis, a disease with significant unmet needs, and that beyond bronchiectasis, it offers additional opportunity in a broad range of neutrophil driven diseases. Following James' presentation, we will provide a more detailed look at the commercial opportunity and strategy for brincicatin, and then we will open the call for your questions. With that, let me now turn the call over to James.
Thank you very much for that introduction, and thank you all for joining the call to talk about these very exciting results of the Phase II randomized double blind placebo controlled trial of the DPP1 inhibitor, Bransokitiv, in patients with bronchiectasis. I'm going to talk you through the WILLOW study results and what I think they mean for the treatment of people with bronchiectasis and also potential applications in other diseases. You should have the slides in front of you. I'll mention which slide I'm going through as we present. So I'm starting on Slide 3.
On Slide 4, I declare that I have worked with InnsMed both in the WILLOW study and also in the context of consultancy and grant funding for other studies. So starting on Slide 5, I want to introduce the concept of neutrophilic inflammation and why it's so important that we have drugs available to target neutrophilic inflammation. Neutrophils are our predominant inflammatory response to bacterial infection and other types of infection, but they also contribute to multiple inflammatory diseases. These include neurological diseases like Alzheimer's disease and stroke, lung diseases such as those that we're discussing today, bronchiectasis, but also COPD, severe asthma, cystic fibrosis, pneumonia and indeed COVID-nineteen, gastrointestinal diseases such as inflammatory bowel disease and many other vascular, neoplastic, autoimmune and other diseases are driven by the presence of activated neutrophils. On the right hand side of Slide 5, you can see a schematic of what neutrophils are supposed to do.
Their primary function is to phagocytose and clear bacteria. So they eat bacteria and clear them through what is a non inflammatory process at the top phagocytosis. What happens in many inflammatory diseases is what's pictured at the bottom of this slide is a process called neutrophil extracellular trap release, where cells literally explode causing damage to bystander cells and perpetuating inflammation. Moving to Slide number 6, we can see that neutrophil elastase, which is a protease that cleaves proteins in the airways, including elastin, is central to the pathogenesis of many neutrophil driven diseases. Thinking now about chronic lung inflammation, on the left hand side in the healthy airway, you can see that neutrophils are able to normally phagocytose bacteria.
On the right, you see the effects of neutrophil elastase in the context of chronic inflammation. Elastase cleaves off the surface of these cells the receptors they need to kill bacteria and elastase also causes the goblet cells, which are the cells that make mucus to enlarge and increase in number, resulting in mucus obstruction, which is what we see in people with COPD, bronchiectasis, cystic fibrosis and many of these other diseases. So many of the key features of inflammatory lung disease can be recapitulated by adding neutrophil elastase into the airway such as emphysema. And so we start to see how important elastase is to the inflammatory process in the lung and why blocking neutrophil elastase could represent an important therapeutic strategy. Moving to Slide 7, we have one final reason why neutrophil elastase is so crucial.
I said that what goes wrong in many of these inflammatory processes is the formation of neutrophil extracellular traps, these webs of DNA that you can see on the left hand side that trap bacteria, but also cause a lot of damage to the lungs, are released by neutrophils when they're inflamed. On the right hand side, you can see a schematic of the signaling pathway that leads to that process and highlighted in the red circle is neutrophil elastase, NE. It's required for releasing DNA from the nucleus of the cells during the final process of releasing neutrophil extracellular traps. So blocking neutrophil elastase could have benefits through preventing its enzyme activity in the lung, but also through blocking the formation of these highly damaging extracellular traps that are involved, as I've mentioned, in inflammatory diseases, but also in cancer and vascular diseases. So having given that background on neutrophilic inflammation, we now move to bronchiectasis in the WILLOW study.
On Slide 8, I discuss the role of neutrophilic inflammation in bronchiectasis. This is a disease where patients produce cough and sputum and have frequent infective exacerbations, which are related to uncontrolled neutrophilic inflammation. Pro inflammatory neutrophil serine proteases including and particularly including neutrophilastase are found in the sputum of patients with bronchiectasis and increase even further during exacerbation. And on the right hand side of this slide, you can see a study that we published in 2017, where we showed that the higher levels of inflammation in the lungs, the higher that level of elastase was, the more likely that patient was to experience an exacerbation. And so elevated neutrophil serine proteases, particularly elastase, are associated with exacerbations, they're associated with poor quality of life, and they also predict decline in lung function over time, so therefore the progression of the disease.
Moving to Slide number 9, Dipeptidylpeptidase 1 or DPP1, also known as kathexin C, is an enzyme that activates these neutrophil serine proteases in developing neutrophils in the bone marrow. DPP1 cleaves an N terminal dipeptide from neutrophil elastase, but also proteinase 3 and kafepsin G, resulting in active neutrophil serine proteases being packaged into granules within the neutrophils. If we move now to Slide number 10, the role of branzocatib, which is a DPP1 inhibitor, is this is an oral small molecule that blocks the activity of DPP1 and therefore interrupts the activation of neutrophil elastase, proteinase 3 and kafepsin G in the bone marrow. The result is individuals taking the drug have neutrophils that are circulating that have reduced levels of these damaging proteases. Preclinical studies have demonstrated that this drug can significantly reduce all three of these neutrophil serine proteases and Phase 1 studies conducted in healthy volunteers have shown reductions in blood levels of neutrophil serine proteases.
And that provides the context to the investigation of this drug to reduce exacerbations in patients with bronchiectasis. Moving to slide number 11, we can see the design of the WILLOW study. This is a randomized double blind placebo controlled trial testing 2 doses of brenzotiv, testing 10 milligrams once daily and 25 milligrams once daily against placebo. After a 6 week screening period, patients were randomized, stratified by the presence of Pseudomonas aeruginosa or the use of long term macrolides, and that's because both of those factors are important predictors of morbidity and exacerbation rate in the population, so important that they're balanced. Patients were then seen at day 1, week 2, and then weeks 4, 8, 12, 16, 20, and 24 for an overall 24 week treatment period.
There was also 4 weeks off treatment in order to look at the dynamics of neutrophilic inflammation off drug. The primary outcome of the study was time to first exacerbation over 24 weeks, and the key secondary respiratory symptom scale, which is a validated symptom questionnaire, change in the post bronchodilator percent predicted FEV1 and changes in sputum neutrophil last days from baseline to the on treatment levels. If we move to slide number 12, you can see the eligibility criteria for the WILLOW study. This study included adults between the age of 1885, who had a BMI above 18.5 and had both a clinical syndrome of bronchiectasis and a CT scan demonstrating bronchiectasis. Patients had to have at least 2 exacerbations in the previous 12 months, and that's in order to enrich the population for frequent exacerbators with the primary outcome being exacerbations.
Patients were also required to be able to provide a sputum sample at screening and to have a sputum color graded as mucapurulent or purulent screening. And that's a marker of neutrophilic inflammation and enriches the patients most likely to respond to an anti neutrophil or a neutrophil blocking therapy. Patients were excluded if they had CF or other less common causes of bronchiectasis. They also were excluded if they had nontuberculous mycobacterial infection or ABPA. Patients were not allowed into the study of their primary diagnosis with COPD or asthma, but as you'll see in a moment, some patients were in the study who had a secondary diagnosis of those two conditions.
Patients were also not allowed to participate if they had a disease called Papillon Lefebvre syndrome, which is a rare condition caused by congenital absence of DPP1. It presents usually in childhood with thickening of the skin called hyperkeratosis, skin infections, and gingivitis or periodontitis. This is a very uncommon condition, but as you'll see when we come to the safety section, we did look for manifestations of this disease, given the mechanism of action of branzocatib. If we move to Slide 13, you can see the flow of patients through the WILLOW study. 416 patients were screened to have 256 patients eligible for randomization, 87 were randomized to placebo, 82 to the 10 milligram Benzocativ dose, 87 to the 25 milligram Benzocativ dose, and more than 80% of patients completed the study with the highest rate of dropouts being in the placebo group.
Moving to Slide 14, this shows the baseline demographics and characteristics of the population, which is very typical of patients with bronchiectasis in the United States or Europe with a mean age over 60 and predominantly female. I mentioned already that a proportion of these patients had a past history of COPD or asthma as a secondary diagnosis. And we've highlighted on the slide in red some important characteristics at baseline. 1 third approximately of the population had Pseudomonas aeruginosa colonization, between 12% 18% were on long term macrolide therapy, and between 28% 41% of patients had a history of 3 or more exacerbations per year. Looking specifically at the exacerbations at baseline, notice that there is an imbalance with more frequent exacerbators in the 25 milligram group.
In terms of the levels of sputum neuterophil elastase, we used 3 levels based on that publication from 2017 I mentioned in the introduction, and patients were reasonably distributed between those who had a level below limit of quantification, which is BLQ, those from lower level of quantification to 20, and those who are above 20, which is a very high level of neutrophil elastase and was associated with the highest risk of exacerbation in our previous study. But now moving to the key results, we're on to Slide 15, and this is the primary endpoint of the time to first bronchiectasis exacerbation. And here the trial met its primary endpoint at both of the doses tested. Renzocativ significantly prolonged the time to first exacerbation versus placebo at the 10 milligram dose with a hazard ratio of 0.58, p value 0.029. At the 25 milligram dose, the hazard ratio is 0.62, which was also statistically significant.
And you can see the Kaplan Meier curve there clearly showing the difference between the 2 Brenzocativ arms and placebo. Moving now to Slide 16, we have the key secondary endpoint, which was the exacerbation rate over 24 weeks of treatment. On the left hand side of the slide, you can see the proportion of patients who had at least one exacerbation during the study. And here in the placebo group, nearly half of the patients experienced an exacerbation during the trial, and this was reduced to 31% in the 10 milligram arm and that was statistically significant, and 33.3% in the 25 milligram arm, also statistically significant. Looking at the annualized rates, you can see that the background annualized rate in the placebo group was 1.37 exacerbations per patient per year.
At the 10 milligram dose, the rate was reduced to 0.88 per patient per year and that difference was statistically significant. The rate was also numerically lower with the 25 milligram branzocatib dose, but as you can see from the p value on the slide, this difference was not statistically significant. I'm moving now to slide 17, which shows sputum neutrophil elastase concentrations. Remembering that this drug blocks the formation or the activation of neutrophil elastase and other proteases in the bone marrow. You can see here the mechanism of action highlighted in this slide.
So in the top line, you can see the placebo group where the neutrinoatrial furlastase remains essentially stable across the study. But in the blue and the green lines, you can see that over 4 weeks, there's a dramatic fall in the levels of sputum neutrophil last days at both the 10 milligram and the 25 milligram dose with the impression of a greater effect of the 25 milligram dose on the sputum neutrophil last days. That's sustained through the 24 weeks of treatment and then the levels of inflammation return to baseline after 4 weeks off treatment. The left hand side is a log scale and so the levels of reduction of sputum neutrophilastase here are really quite striking. Now moving to Slide 18, we see data that really shows the importance of inflammation in driving exacerbations in bronchiectasis.
I'm now showing an analysis just of the patients who are in the branzocatib groups. And here we've pooled the 10 milligram and the 25 milligram arms together. The line at the top, with the green confidence intervals is patients that managed to achieve complete suppression of inflammation during the study on branzocatib. So these patients had a neutrophil elastase below the limit of quantification after baseline. And you can see the exacerbation rate in that group is very low.
In the other group, with the orange confidence intervals, you can see those are the patients that had consistently levels of neutral elastase that were quantifiable post baseline. So they failed to suppress their inflammation with branzotib. And you can see the difference in the rates of exacerbation between these groups. The hazard ratio is 0.28, a striking difference in outcome between these two groups, showing that if you manage to suppress inflammation with this drug with branzocatib, you're very unlikely to experience exacerbations. Moving now to additional secondary endpoints on Slide 19, I'm showing the change in post bronchodilator FEV1.
And here, although we didn't perform any statistical testing because of the hierarchical nature of the statistical analysis plan, In the placebo group, you can see a reduction in lung function over the course of the study of minus 1.8%. The patients with bronchiectasis do experience an accelerated decline in lung function over time, and that's seen here in the patients in the placebo group. And so I consider it very encouraging that the rate of decline in the 10 milligram and 25 milligram arms is only minus 0.3%. So while this is not statistically significant, it is encouraging for larger and longer studies because 24 weeks is not optimal to evaluate long term changes in lung function. So the other key set of data that we need to talk about is safety.
And on Slide 20, we see the start of the safety summary. And the message here is that in the top three lines, you can see that treatment emergent adverse events and particularly treatment emergent adverse events resulting in treatment discontinuation were numerically higher in the placebo group. Serious treatment emergent adverse events were also numerically higher in the placebo group at 22.4% compared to 13.6% and 11.2% in the 2 burnsecutive treatment arms. The most common adverse events across the whole study population were cough, headache, increased sputum, dyspnea, exacerbation of bronchiectasis and diarrhea, and some of those adverse events are more common in the bronzocative treatment arms. So this slide would give you the impression that the frequency of adverse events is quite similar between branzotiv and placebo.
On the next slide, which is slide 21, we look at the adverse events of special interest because I mentioned already that there is a human condition Papillon LaFebre syndrome caused by absence of DPP1. And so it's important for us to look and see if there is any evidence of adverse events that resemble that condition with Brinzocative treatment. And so the adverse events of special interest were skin, dental and infection related. And you can see a numerically higher rate of adverse events of special interest at both the 10 milligram and the 25 milligram Renzocativ groups, with an increase numerically in skin adverse events, particularly with the 25 milligram and also reported dental adverse events. But it's important to understand what this data means.
Patients were followed up very carefully in the trial by a dentist because of the concerns about periodontitis. And so change in periodontal pocket depth is an outcome observed by a dentist. And you can see that that was numerically higher in the brinzocatively 10 milligram and 25 milligram arm. But the last line of this table is the serious periodontitis that would be of clinical concern, and that's a change in a pocket depth with an increase to greater than or equal to 5 millimeter absolute depth. And that was very similar between the three groups.
The main skin effect of Papillon Lefebvre syndrome is hyperkeratosis, and here we saw very reassuring data. Hyperkeratosis was only reported in 1 patient in the placebo arm, 3 patients in the 10 milligram Brenzocativ arm and 1 in the 25 milligram arm. All of these resolved or improved at the end of the study and none required interruption of study drug. So we see reassuring data around the dental adverse effects and reassuring data around the issue of hyperkeratosis. So moving to Slide 22, Renzocatib in conclusion at both the 10 milligram dose.
We also saw a very clear dose dependent reduction in neutrophilastase levels in sputum, supporting the mechanism of action of branzocatib to reduce neutrophil serum protease activation. Both doses were well tolerated with an overall safety profile comparable to placebo. And this is really exciting data because we have no licensed therapy for people with bronchiectasis. And if these results were confirmed in a Phase 3 trial, this represents the first in class novel non antibiotic therapy to prevent exacerbations for people with bronchiectasis. Moving to Slide 23, I think it's important that I emphasize just how big a development this would be for people with bronchiectasis.
We understand this disease in terms of this vicious cycle where patients have, on the right hand side, abnormal mutacillary clearance, which can only be improved by performing regular airway clearance exercises. Despite that, patients develop bacterial infection, which requires frequent courses of antibiotics and often long term treatment with macrolides or inhaled antibiotics. And that infection drives chronic inflammation that ultimately leads to airway destruction. And we completely lack in the guidelines and in our clinical armamentarium any therapy that can directly target inflammation. So, BRENZOCATIVE would represent a completely new type of therapy for patients with bronchiectasis that doesn't carry the risks of antibiotic resistance that comes with things like macrolides and inhaled antibiotics.
Moving to Slide 24, bronchiectasis is only the start of the story around chronic neutrophilic inflammation. There is no other medication at the moment that directly targets neutrophilic inflammation in the lung or indeed outside the lung. There's an unmet medical need for an anti neutrophil therapy in bronchiectasis, in COPD, in severe asthma, in cystic fibrosis and in acute respiratory infections including COVID-nineteen. There's an urgent need for these types of therapies in chronic neutrophilic diseases outside the respiratory tract as well. Previous approaches to target neutrophilic inflammation such as CXCR2 antagonists or LTV4 have been unsuccessful because they try and reduce the numbers of neutrophils.
What's special about this approach is that it reduces the damaging effects of neutrophil serine proteases without affecting our ability to fight off infections. And so this has potential applications in multiple diseases. Moving to Slide 25, this is just one example of where we can look at new avenues for branzocatib and for this mechanism of action. In collaboration with Insmed, I'm currently conducting the STOP COVID-nineteen study. STOP COVID is an investigator initiated study of branzocatib targeted at patients with COVID-nineteen infection.
It's a placebo controlled trial using the 25 milligram dose where the primary outcome is the WHO recommended clinical status at day 29 with other secondary endpoints, including requirement for mechanical ventilation and mortality. This is a multicenter study across the U. K. That will enroll 300 patients. There's already very strong data implicating neutrophil serine proteases and neutrophil extracellular traps in pneumonia, ARDS and in COVID-nineteen, and we look forward to successfully completing this study and sharing the data with you.
So I'd like to finish on Slide 26 by acknowledging all of the patients, their families and all of the investigators and study sites that contributed to the WILLOW study. Undertaking a study like this in an orphan indication is a huge undertaking, and all of the people that contributed can be very proud of the results that have been delivered. And for Insmed, full credit for having invested in this mechanism of action, which is so key to so many diseases, and also to acknowledge writing support for developing these slides in the study publication from Meditech Media. And with that, I will hand back to Will. Thank you very much for giving me the chance to share these results with you.
Thank you very much, James. We are excited as well by these results and the clinical impact that brincicativ may have in bronchiectasis, COVID-nineteen and indeed other neutrophil driven diseases. Turning to Slide 27. Over the next several minutes, I'd like to comment on some of the broader potential applications for brincicatib as a novel first in class neutrophil immunomodulator. I will then delve into the market dynamics for our lead indication bronchiectasis and the multiple synergies we see with our existing ARIKAYCE franchise.
At a high level, we believe we have a unique opportunity to address a longstanding unmet need in bronchiectasis, while laying the groundwork for significant expansion potential, both globally and in additional indications. Turning to Slide 28. In his remarks, James reviewed the mechanism of action for brensikatib. We believe that brensikatib represents an entirely new way to address a broad range of diseases where high neutrophil activity is a component of the disease process. These include rare diseases like cystic fibrosis, alpha-one antitrypsin deficiency and granulomatosis with polyangiitis or GPA, as well as more common diseases like inflammatory bowel disease or IBD, lupus, rheumatoid arthritis, COPD and asthma.
This broad array of potential indications represents opportunities both for AinsMed to take forward ourselves as well as those where we may leverage a partnership. Importantly, as shown on Slide 29, we have already initiated preclinical work that has generated positive results in several potential therapeutic areas. In an animal model of lupus nephritis, for example, brimsocatib showed a beneficial effect on renal function and kidney damage. For IBD in an animal model of colitis, brincicatib showed beneficial effects on intestinal damage and intestinal function. And for GPA and in vitro studies, human neutrophils treated with brincicatib showed decreased surface expression of proteinase 3, which is the target of the anti neutrophil cytoplasmic antibodies or ANCA's that are characteristic of GPA.
While there is more work to be done, we believe there is a meaningful opportunity to build a pipeline around brincicaptib addressing a number of unmet medical needs for patients, thereby providing significant commercial potential for the company and meaningful value creation for our shareholders. Moving on to Slide 30. Of course, as you know, our initial efforts are focused on bronchiectasis, driven by the strength of the WILLOW data and the potential to address the unmet need in this indication. James touched on the vicious cycle of mucociliary dysfunction, infection and inflammation that defines bronchiectasis progressively resulting in permanent lung damage. The typical patient is older and female, and notably, over 60% also have an NTM infection.
Patients with bronchiectasis experience an average of 2 exacerbations per year with more than 1 third having 3 or more per year and approximately 1 quarter requiring hospitalization. The demographics of the WILLOW study reflect this moderate to severe course of disease that the majority of patients face. And as James described, the consequences are profound. Patients face a lower quality of life and impaired lung function that leads to about a twofold increase in mortality compared to the general population. Today, there are no approved therapies specifically targeting this chronic and serious pulmonary disease in the U.
S, Europe or Japan. We believe that brincilcatib, which has been shown to significantly prolong the time to first exacerbation and reduce the frequency of exacerbations, could address this clear unmet need. Turning now to Slide 31. The FDA has recognized the strength of the WILLOW data and our potential to address this urgent need by recently granting brincocatib breakthrough therapy designation for patients with non CF bronchiectasis. This designation underscores the serious and life threatening nature of the disease and the potential of brincicatib to provide substantial improvement over existing therapies.
Importantly, this designation provides a number of benefits, including eligibility for rolling and priority review and enhanced dialogue with the FDA. We are pleased to note that this is the 2nd breakthrough designation that Insmed has been granted after receiving the same designation for ARIKAYCE. As we have shared previously, we expect to initiate our Phase 3 program in bronchiectasis in the second half of this year following alignment with the FDA on trial design. Let me now turn to the market landscape for bronchiectasis as shown on Slide 32. In the U.
S. Alone, an estimated 340,000 to 520,000 patients have bronchiectasis. Estimates suggest a similar per capita prevalence in Europe. And while the estimated prevalence of the disease in Asia lacks full consensus, rates are reported to be significantly higher with an estimated 1,000,000 to 5,000,000 patients in China alone. We expect these numbers will evolve as we sharpen our understanding of the global market.
As shown on Slide 33, we believe the prevalence may actually be substantially higher globally given the under diagnosis of bronchiectasis. Importantly, there is significant overlap between bronchiectasis and COPD and asthma. Estimates again vary with anywhere from 650,000 to 9,000,000 U. S. COPD patients also having bronchiectasis.
This represents a range from as few as 4% to as many as 54% of COPD patients depending on the literature. In asthma, the overlap of patients who also have bronchiectasis falls between 450,000,675,000 patients in the U. S. Or 2% to 3% of asthma patients. Even at the low end of these ranges, the data suggest a larger bronchiectasis patient population in the U.
S. Than often cited. When we looked at the overlap between COPD and asthma and bronchiectasis on a global scale, shown on Slide 34, the potential market size could be quite substantial. Based on its mechanism of action, brincocatsib may also have potential as a treatment for these diseases. Despite a wide variety of approved therapies for both asthma and COPD, a significant unmet need remains with a sizable population of patients who are not fully responsive to existing treatments.
For asthma, many patients could benefit from a treatment that could reduce exacerbations. And COPD remains the 3rd leading cause of death in the U. S. Behind only heart disease and cancer. With no disease modifying treatments available, the World Health Organization predicts that COPD will be the 3rd leading cause of death worldwide by 2,030.
If brincicatib is shown to have an impact in some patients with these overlapping conditions, it would certainly represent a meaningful advancement. Now let's turn to our commercial focus and readiness for brincicatib in bronchiectasis, shown on Slide 35. The Insmed team is uniquely positioned to commercialize brincicatib given the synergies that exist between bronchiectasis and NTM lung disease. Based on initial research and our ARIKAYCE experience, we know that bronchiectasis patients are typically seen by pulmonologists, allowing us to leverage our existing commercial infrastructure. In fact, in the U.
S, nearly 80% of the highest volume bronchiectasis treaters are already called upon for ARIKAYCE. Based on preliminary assessments of this overlap in health care providers and using approximate numbers, we anticipate that a modest 30% increase to our current 70 person sales force would allow us to reach 70% of the bronchiectasis community. In addition, there is a meaningful overlap in patient populations with over 60% of bronchiectasis patients also having an NTM infection. We also see strong alignment in the geographies where these two diseases tend to be prevalent. Based on our current U.
S. ARIKAYCE sales footprint, we know that the centers of excellence treating NTM patients are the same as those treating bronchiectasis patients. We have strong existing relationships with these key centers and a solid grasp of the regional treatment landscape. Now let's turn to Slide 36. The work we've done over the past several years to build a commercial infrastructure to reach and support the NTM lung disease community can be rapidly mobilized to support a potential launch of brincicatib for bronchiectasis in the U.
S, Europe and Japan. Backed by the trajectory of the ARIKAYCE launch, we are well equipped with key learning in the upper disease space. Notably, our experience in patient identification and executing disease awareness campaigns as well as our ERICARE support program, which aims to support this patient profile, positions us for success. Our initial payer research also supports the potential of the brincicatib product profile, an FDA approved product that could modify the course of disease by interrupting the inflammatory cascade and thereby reducing exacerbations would be viewed very positively and represent a major therapeutic advance, particularly since exacerbations often lead to doctor or hospital visits. In fact, in the WILLOW study, patients on brincicatib had fewer hospitalizations than those on placebo due to having experienced fewer exacerbations.
We believe this offers a strong value proposition for brincicatib in bronchiectasis. While we are still conducting pricing research, there are clear precedents for specialty products in the asthma space that provide a useful benchmark. For example, Fasenra, which is approved to treat eosinophilic asthma, addresses a population of several 1000000 people and costs between $30,000 to $40,000 a year. We have broad patent protection into 2,035 in the U. S, Europe, Japan and China with the opportunity for additional patent extensions and multiple development opportunities coming into focus.
And we believe we are currently the only company in Phase 3 development with a novel non antibiotic approach that aims to directly impact the inflammatory cycle of bronchiectasis rather than treat only the infections associated with bronchiectasis. Historically, drug development efforts seeking to treat the infection have proven unsuccessful, highlighting the challenging nature of this disease. I'll end prepared remarks with Slide 37. Taking a step back, we believe brincicatib represents a true game changer in the treatment of a broad range of neutrophil mediated diseases. With a once daily small molecule treatment, we may be able to address the underlying disease process implicated in a number of diseases, from rare diseases with no treatment options to more common indications in need of true innovation.
There is tremendous opportunity inherent in this unique asset, and we have the expertise and vision to take full advantage of the potential offered by brincicatib in bronchiectasis and other potential indications, including leveraging partnerships where and when appropriate. We are very excited about this program and look forward to providing updates as we advance our efforts. Let me close by thanking James, our other study investigators and the patients who participated in the WILLOW study. I'd also like to thank the dedicated Insmed team for their continued execution. We believe we are advancing a pipeline of high value opportunities in areas of stark unmet medical need, and we are thrilled with the progress we've already made with brincocatib.
With that, I'd like to open the call to questions. Operator, can we take the first question, please?
Our first question today comes from Adam Walsh with Stifel.
Hey, guys. Thank you for taking my questions and I appreciate the presentation. Doctor. Chalmers, the first one for you. On the key secondary endpoint of the pulmonary exacerbation rate over 24 weeks, the 10 milligram dose did a little bit better than the 25 milligram dose.
And as it turns out, the 25 milligram dose cohort had higher rate of more than 3 pulmonary exacerbations at baseline. So that is one thing that could explain. Other docs that we've talked to brought up the potential for a plateau effect with this drug. And I just wanted to get your thoughts on what you think we're seeing here and whether you believe the 25 milligram dose has been properly identified as the appropriate go forward? Thank you.
So very good question. I think that the trial is not big enough to make any firm conclusions about the superiority of one dose over the other. The trial was designed to show differences with placebo. Having said that, I think that what you see is a substantial reduction in levels of neutrophilastase, which is greater with the 25 milligram dose, which does give us some pause to think over a longer period of time with a larger study population, would we see additive benefits of the higher dose? I think we need to wait for Phase 3 to see that.
I'm not concerned about the differences in terms of exacerbation rates between the 10 and the 25 milligrams, we're talking about very few events that differentiate those 2. And as you rightly pointed out, the 25 milligram dose started off with a higher number of frequent exacerbators. And so it's actually remarkable that such good results were obtained despite having a few more severe patients in that population. So I think in summary, I think there's evidence to support the use of both doses and I think we need to wait for the results of the Phase 3 before we make any final decision on dose. Great.
And then a follow-up for you, Doctor. Chalmers. In terms of Slide 19, I believe it is, the change in post bronchodilator PP FEV1 at week 24. We had talked to some KOLs previously who thought that the FEV1 measurements, the functional measurements would be kind of important to their assessment of the drug. And I wondered if maybe you could talk a little bit more about this slide.
One of your colleagues had previously said they're looking for an absolute minimum change of 200 milliliters and a 12% improvement from baseline. What do you think is clinically meaningful and how does the Slide 19 help us understand that? Thank you.
Sure. So I think it's really important that we remember that this is bronchiectasis, it's not asthma and it's not cystic fibrosis. So in other diseases FEV1 is used as the primary endpoint because they're diseases of bronchoconstriction where FEV1 improvements represent benefit. In bronchiectasis, no drug has ever been shown to change FEV1. All of the antibiotic studies, even the macrolide studies, nothing shifts FEV1.
And so the fact that we see such a striking difference, even if it's not statistically significant, is quite remarkable here. So there's something going on with this drug that it seems to be able to slow the rate of FEV1 decline, but we need longer term studies to see if that's a really true signal. But FEV-one ultimately is not going to be the way that we judge this drug over a 12 month period. It's going to be exacerbations and related endpoints. But the I find this data very encouraging because, as I mentioned, nothing else seems to have prevented lung function decline historically.
And if there's even a signal that brenzocatib can do that, it bodes really well for the Phase 3 study.
And if I could really quickly one for Will. Will, just on the I know GSK had a DPP1 inhibitor as well and they had some, I believe, skin ease of special interest that maybe were related to durability or duration of treatment. I'm just wondering, I mean, what are you hearing from the regulatory perspective on kind of DPP-one inhibitors and what they want to see in terms of safety on the skin manifestation side? Thank you.
Yes. So we are having our meeting with FDA in the middle of the year. So it's in the not too distant future, but we haven't had it yet. I don't anticipate this being a point of controversy or difficulty. And I think the breakthrough therapy designation points in the direction that they probably view it the same way, particularly since this is a division that's supposed to be probably occupying majority of their time on COVID-nineteen.
But having said all that, yes, the GSK compound, and there's not a lot of data out there about it, but it was a more as I recall it, it was a more potent DPP-one inhibitor and it was non reversible. And I think what we have here, for lack of a better way of saying it, and I'd invite James to comment on this if you'd like, if you know the GSK compound at all, but this is sort of it feels like we may have found the Goldilocks level, where DPP1 inhibition could play a clinically beneficial role, but without triggering symptoms that are reminiscent of papionnofib?
Yes. I'll come in and say, I use exactly the same phrase when I'm talking about this drug. It's about finding the Goldilocks zone. You don't want to completely inhibit DPV1 because that's papillomavvera. And you've seen from the elastase data that I presented, the 25 milligram dose reduces, but doesn't completely remove protease activity.
And so I think we found the perfect balance between inhibiting neutrophil serine proteases without inducing the potential adverse events. So Goldilocks is absolutely right.
Got it. Thank you.
Our next question comes from Ritu Baral with Cowen.
Good afternoon, everyone. Thanks for taking the question. One for Doctor. Chalmers. Per your presentation today with ATS, you mentioned that there was no difference between the analysis, which stratified for background organisms specifically colonization by Pseudomonas or even background antibiotics.
Are you surprised by this? Was there any trend? And I guess I was particularly surprised that there was no additive effect with the background antibiotic. Can you talk to maybe the mechanism behind this?
Absolutely. So we conducted a large number of subgroup analyses to try and understand if there was a responder population. And I wasn't surprised at all that we didn't find 1. Neutrophilic inflammation is a near universal finding in people with bronchiectasis, regardless of which pathogen they're colonized with or what background medication they're on. And even drugs like macrolides, they have an effect, but they don't directly target neutrophilic inflammation.
So the inflammation is still there. And therefore, the risk of exacerbation is still there. So I'm not at all surprised that the drug works across a range of patients with bronchiectasis because this is such a universal mechanism. And that's what we've seen previously when we've been studying the disease is that in the sputum of every patient, whether they've got Pseudomonas or Haemophilus or any other pathogen or whatever background therapies they're on, they still have detectable neutrophil last days and they still have these neutrophilic exacerbations. So I think the subgroup data being so consistent is really encouraging in terms of this being a drug that we can use across a very large population of bronchiectasis patients.
Got it. And then, was there any secondary endpoint measure that may have reflected severity or improvements in severity of the exacerbation episodes itself. You'd also mentioned in your presentation that there was I believe there was no impact on the QLLB respiratory component, but there was on the non respiratory component. Can you go go through the quality of life observations that you saw? Thanks.
Absolutely. So in terms of your first question of changing severity of exacerbations, there isn't really an established scale for measuring the severity of exacerbations, But it was encouraging to see that there were fewer severe exacerbations in patients randomized to branzocatib. So there were 10 severe exacerbations in the placebo group, 5 in the benzocatib 10 milligram and 4 in the 25 milligram group. So although the numbers are small, that's a very encouraging trend to reduction in severe exacerbations. In terms of the quality of life data, I mentioned when presenting the ATS data that there really isn't a validated questionnaire or a questionnaire that we all universally agree is the way to measure symptoms and these outcomes in bronchiectasis.
So we didn't see significant differences in the respiratory symptom domain of the QLB. We didn't see significant differences in the St. George's Respiratory Questionnaire, which is another validated questionnaire. But there were some encouraging results in some of the non respiratory symptom domains in terms of physical functioning, for example,
Pardon me, it looks like we might have lost our connection. Please hold for a moment while we try to get him back.
Sorry, everybody. Hang on for a sec while we track down James. We're going to give the operator about a minute to try and track him down. If she's still in that process, then we'll pick it up from there and move forward with other questions.
And pardon me, everyone. We've rejoined James Chalmers, and I'd like to turn it back over
to Ham. I apologize for I was temporarily disconnected. So just to finish the answer that I was giving on quality of life. So there were some very encouraging changes, nominally statistically significant in physical functioning, in emotional functioning for the 25 milligram dose, and in some of the other domains. And so I think it's something that we need to look at in larger studies, but there are encouraging data that suggests that in addition to the exacerbation benefits, there's also benefits on quality of life.
Our next question today comes from Martin Auster with Credit Suisse.
Hi, everyone. This is Mark on for Marty. Thanks for taking my questions and congrats on the data. For Doctor. Commerce, I just wanted to get a little more clarity.
I'm curious if you were surprised that the drug was effective regardless of baseline neutrophil elastase level? And then as far as thinking about future trials, would you incorporate some baseline neutrophil elastase level as a criteria for enrollment in those future studies? And then I have a quick follow-up.
So it's a really great question. I had thought when designing the study that patients with levels below the limit of quantification would not benefit, and I was wrong about that. And I think we now understand more about the biology of the disease and we know why that is. And it's because patients that have low levels at baseline, even it's undetectable at baseline, when they have an exacerbation, they up regulate their elastase. And if they're on this drug, it prevents them from doing that.
And so it can still prevent a neutrophilic exacerbation even if the patient doesn't have high levels of inflammation at baseline. And that's really good news because it means that a much larger population can respond. I still suspect when we get to Phase 3, we'll start to see some differences depending on baseline, for example, in things like symptoms. But that's speculation on my part, based on experience with other drugs where baseline inflammatory processes do predict outcomes like Fasenra and drugs like that, that have been mentioned on this call already.
Got it. And then assuming the Phase II profile holds in Phase III, I was just curious if you could frame how you would use the drug in your potentially prescribe it to?
Yes. So I think there's something very, very special about this medication in terms of how it would be positioned because it's not an antibiotic and it doesn't have those concerns that we have about things like macrolides. So at the moment, my first line treatment for bronchiectasis is airway clearance. If patients continue to have exacerbations despite doing good airway clearance, your first therapy is a macrolide off label. I think branzocatib becomes your go to drug before the macrolide because macrolides induce antibiotic resistance and they have this issue around non tuberculosis mycobacterial infection, which is a huge issue in the U.
S. And prevents widespread macrolide use. So I think brinzoctave becomes your go to therapy for people with frequent exacerbations, particularly if the Phase 3 shows this kind of magnitude of benefit and potentially disease modification. It's an oral once daily tablet, which means it's much more likely to be preferred over some of the other off label things we use like inhaled antibiotics or hypertonic saline because it's just easier for the patients to use. And so I can see this drug being 60% of my patients, which is my current number of patients that have 2 or more exacerbations per year and would have met the Willow
inclusion criteria.
Our next question comes from Joseph Schwartz with SVB Leerink.
Great. Congratulations on the strong data. I was intrigued by the analysis on Slide 18 showing that patients who achieved a sputum neutrophil elastase below the limited upon a patient had far fewer exacerbations. And also on the prior slide, it showed that neutrophil elastase dropped so much more in the 25 milligram group. So that seemed to be non concordant with the clinical benefits.
And I think somebody asked this before, but I was just wondering if we can talk a little bit more about this. And have you done a response exposure analysis beyond this to see if anything like patient weight or anything might have confounded things? I know that it was discussed that the patients appeared to be more severe than 25 milligram group. What do you do with this information going forward? And do you have any more thoughts on it?
So to directly answer your question, we're just really starting to dig deep into the data around individual patient response. It's important to point out that the measure unusual for the last days is quite variable in sputum because sputum is quite a variable matrix. So we're starting to get a handle on this relationship between the sputumelastase and the response. And what you've seen on Slide 18 is our first real strong evidence that there is a direct relationship between the inflammatory response in the lungs and the frequency of exacerbations. But it's going to take us a little bit longer to understand how that impacts on an individual patient level, which I think is more your question.
And in terms of the differences between the dose, I think that you're absolutely right to point out the 25 milligram seemed to give a greater drop in the neutrophil elastase, but the 10 is also having really striking effects on the elastase concentrations in the sputum and allowing a number of patients to then get below the limit of quantification. And so I think the Slide 17 really shows you that both of the doses are dropping that elastase to below a level that probably your endogenous inhibitors can mop up much of the remaining elastase.
Right. Okay, that's helpful. Thank you. And then, could you talk a little bit about the heterogeneity of bronchiectasis, Doctor. Chalmers?
We hear that a lot from your colleagues. And I'm wondering if there's subsets of patients with certain characteristics that make them more or less likely to benefit or be in need of a drug like brincicatin?
Absolutely. So when we're talking about the heterogeneity of bronchiectasis, we're often talking about the fact that it can be caused by a wide range of different underlying diseases. And so one of the important things to point out about the WILLOW study design is that it did exclude people with immunodeficiency. It did exclude patients with alpha-one antitrypsin deficiency with NTM and with ABPA. And so we focused in the WILLOW study at a much more homogeneous population of frequently exacerbating patients that predominantly have idiopathic and post infective bronchiectasis, which is 80% or more of the European and the U.
S. Bronchiectasis population. But that having that more homogeneous population helps us to understand more about the efficacy of the drug. And what you see within that population is that neutrophilic inflammation is an almost universal feature. And this therapy is therefore working across all of the different subgroups.
So there is heterogeneity in the bacteria, but we don't see any difference in response around bacteria. There's heterogeneity in terms of exacerbation history, but we don't see any difference in the response in the trial. So I think you will hear that when you talk to clinicians, it's a heterogeneous disease. But one of the universal features across all the causes is neutrophilic inflammation. And that's why I'm so excited about this therapy because I think it cuts through a lot of that heterogeneity, that clinical heterogeneity to get to the inflammatory process, which really isn't that heterogeneous.
Thank you very much.
Our next question comes from Matthew Harrison with Morgan Stanley.
Hi, Will and Doctor. Traumels. Thanks for taking the question. This is Connor Meehan on for Matthew. So we just had a couple of questions mostly on NxTEX.
Will, you mentioned you have the FDA meeting coming up next mid year. But I guess we're just wondering what your plans between now and then and then following that meeting before the Phase 3 are? And then I guess could you provide a little bit more insight on how you plan to power the study, the Phase 3 and I guess how you plan to approach dosing? And then just finally, are there any expectations for special monitoring in the Phase 3 such as dental? And if the adverse events of special interest that were highlighted today, I guess if there's any concern for those coming back in similar levels when the Phase 3 reads out?
Thanks very much.
Sure. So, in each of these questions, it's all about how can we get from where we are now to the kickoff of this Phase 3 study. I think we're this Phase 3 program, we are super excited about these data. And I think, as you've heard from James today, but I think you will also hear from others as they become more familiar with the data, the promise of this is demand that we get on it right away. So next steps have already begun.
We have been in trial design discussions for some time. We think we've got some ideas. But issues like powering, those will come after the conclusion of our discussion with regulators. Their input is obviously incredibly important. And with breakthrough therapy designation, that process should be smooth and pretty straightforward.
With regard to issues like dosing, our plan right now is take 10 and 25 forward. Again, we'll have a discussion with FDA and others to ensure that there is a good alignment around that, but I don't anticipate that being problematic. And then I think the question about monitoring adverse events of special interest, again, regulatory input will be critical there. But I think for how we think about this program, and you heard James say it, and I'll invite him to comment again now, we don't see anything here that would be preventative for this drug to find use in bronchiectasis if it would replicate these same results in Phase 3. But let me just put it over to James and ask him for his perspective on that.
Yes. So I absolutely agree. I think the safety is very reassuring and avoids a number of the safety issues that we have with other drugs that we use off label like the macrolides that I've mentioned before. So I think if the efficacy and safety data that we've seen in the WILLOW study were replicated in the Phase III study, this would be, as I mentioned already, the go to drug potentially for frequently exacerbating patients.
Does it answer your questions? It does. Thank you very much. You're welcome.
Our next question will come from Gregg Svanovich with Goldman Sachs.
Great. Thank you for taking my questions and thanks for the presentation as well. I've got actually three questions for Doctor. Chalmers. My first just has to do around the dosing for brinsocatib and whether you feel based on this data there is a need to potentially explore a higher dose of brincocatib.
So that's my first question. My second question just has to do with brincocatib perhaps and other pulmonary conditions such as asthma. And I'm wondering if you can comment on what the bar for success would look like in asthma or what would look good for brenzocatib in a condition like asthma or COPD? And then my last question just has to do with the STAP COVID-nineteen trial. I mean, I think it's an interesting trial.
I'm going to assume none of us on the sell side have it in our models. But I guess the question is, given where COVID-nineteen is right now in the U. K, how are you thinking about the progress of that trial, whether it be enrollment? I don't know what cases are like in the U. K.
Right now. And those would be my 3 questions. Thank you.
Those are very, very good questions. So I'll take the final part first, which is around COVID-nineteen. So we've started enrollment to the study and we're enrolling across multiple centers. The epidemiology of COVID-nineteen in the U. K.
Is such there's still several 100 cases being diagnosed each day within the UK. We're hoping we don't experience a second wave as other countries like Singapore, Iran and others have, but I think we need to prepare for that and we've built that into our projections around enrollment. So we're aiming to complete enrollment to that study by the end of the year so that we have results this year. Your first remind me what your first question was?
Yes, it was around whether it was
yes, whether it was a
higher dose. Yes, whether
it was a higher dose. Yes. So my feeling is that what you see on Slide 17, which is the reduction in sputum neutrophil elastase is that the 25 milligram dose is taking this down to levels that are below the level where we see an increased risk of exacerbation. So if we measure sputumutumethylastase in patients with bronchiectasis coming through my clinic and we find levels such as those you see on the slide, that's a patient with well controlled disease. And it was discussed in response to one of the previous answers that you don't want to take this down to 0 because we don't want to risk replicating the features of papionnofebra.
And so I think having found the Goldilocks zone, I wouldn't personally advocate trying to find a higher dose. I think the benefits that we've seen in the 25 milligram, if they were replicated in a Phase 3 study, this would be a very useful addition to the armamentarium.
And then the other question was just about the bar for success and or what good would look like with brincocatib in larger pulmonary conditions like asthma, COPD?
So I think asthma is a really interesting indication. So we know that in eosinophilic asthma, the biologics are now having a major effect on exacerbations, but there's this 30% of patients with severe asthma who have neutrophilic disease. They don't qualify for any of the biologics, either anti IgE or anti eosinophil therapy. And those patients at the moment don't have a therapy. And they have features clinically that are very similar to people with bronchiectasis often with cough and sputum neutrophils in the airways.
Their levels of elastase are lower than patients with bronchiectasis. And so you might in neutrophilic asthma, in that difficult severe asthma population. And again, your endpoint would be exacerbations, because the mechanism of exacerbation is the same as it is in people with bronchiectasis. And you mentioned COPD, The overlap in inflammation between COPD and bronchiectasis is really striking with published proteomic data that shows that at a cellular level, the inflammation is virtually identical. And so there's no biological reason to believe you wouldn't replicate the WILLOW data in a COPD population if you design that study right.
Thank you.
This concludes our question and answer session. And I would like to turn the call back over to Will Lewis for any closing remarks.
Thank you very much. Thanks, everyone, for joining us. But a special thank you to James, having done his ATS presentation, for jumping on the call and fielding these questions, helping us to understand these exciting data. Take care, everyone. Stay safe.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.