Insmed Inc (INSM) 2021 Q4 法說會逐字稿

Welcome to the Insmed Fourth Quarter and Full Year 2021 Financial Results. My name is Juan, and I will be coordinating your call today. (Operator Instructions)

I will now hand over to your host, Eleanor Barisser, Investor Relations at Insmed to begin with. Please, Eleanor, go ahead.

Thank you, Juan. Good morning, and welcome to today's conference call to discuss our full year financial results for 2021 and to provide a business and pipeline update.

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 Securities and Exchange Commission, which are available through the SEC's website at www.sec.gov or from our website for information concerning the risk factors that could affect the company. The information on today's call is not intended for promotional purposes and not sufficient for prescribing decisions.

Joining me on today's call are members of the Insmed executive management team, including Will Lewis, Chair and Chief Executive Officer; Dr. Martina Flammer, Chief Medical Officer; Roger Adsett, Chief Operating Officer; and Sara Bonstein, Chief Financial Officer.

Let me now turn the call over to Will Lewis for prepared remarks. Upon completion of those remarks, we will open the call up for your questions.

Thank you, Eleanor and Good morning, everyone. Today is a very exciting day for us at Insmed. We are going to share with you a robust set of updates that will clarify how we are thinking about our program, catalysts, commercial franchise and capital allocation over the next several years to support our mission of transforming the lives of patients with serious and rare diseases.

At Insmed, we are building what we believe is one of the few companies in our industry capable of producing potentially multibillion dollars of revenue by the end of this decade. During the course of today's call, we are excited to review the path we will be following as we pursue this ambitious goal. Our strategy is centered on developing medicines that have a significant positive impact on patients' lives. Today, Insmed has 7 ongoing mid- and late-stage clinical trials, commercial operations in 3 territories around the globe and a research engine working behind the scenes to identify the most promising early-stage candidates by harnessing innovative technologies.

We have segmented all of this work into 4 pillars. The first of these pillars is the ARIKAYCE franchise, our marketed product for the treatment of refractory MAC lung disease, where we benefit from a commercial footprint in the U.S., Europe and Japan. As these launches mature, we intend to grow revenue globally by at least 30% this year compared to 2021. In parallel, our frontline clinical trial program is advancing to support full FDA and select international accruals of ARIKAYCE in newly diagnosed NTM patients. This frontline indication represents a multifold increase in the addressable opportunity compared to the refractory setting alone. The ARISE study, which is the first of the 2 studies needed on our path to approval is currently 50% enrolled, and we anticipate enrollment to be complete this year with topline data in the first half of next year. We also anticipate the second study, ENCORE, will be fully enrolled next year.

For our second pillar, Brensocatib, our DPP1 inhibitor, the ASPEN trial exploring the potential of treatment of bronchiectasis is now 50% enrolled, ahead of internal projections, and we anticipate it will be fully enrolled by approximately this time next year. There is real enthusiasm for this trial around the world as this rapid rate of enrollment testifies. In addition to ASPEN, the Phase 2 PK/PD study in cystic fibrosis patients is underway, and we anticipate topline data by the end of this year or early 2023. In line with our strategy to build a portfolio around neutrophil-mediated diseases using our DPP1 inhibitor, we are excited to report that we have identified the next 2 potential indications for Brensocatib along with Phase 2 clinical trial designs for their exploration. You will hear more about these later on today's call.

Our third pillar, TPIP, is a specialized treprostinil prodrug formulation with 3 parallel Phase 2 programs underway with an initial focus on potential treatments for PAH and PH-ILD. We will also review those trial designs later on the call.

Finally, translational medicine is our fourth pillar. Led by several world-class teams, our research engine is working with exciting new technologies to identify the next round of Insmed's early-stage pipeline candidates in the serious and rare disease space. Within this framework, we intend to generate, on average, one new IND per year. We look forward to hosting a detailed research day in the second half of this year to update you on our progress.

Set against the backdrop of one of the more challenging healthcare markets in recent years, I believe Insmed is poised to weather the storm of these turbulent times. Our goals are ambitious, but we have been deliberate in our pursuit, and we have a track record of achieving what we set out to do. The next stage of our growth will depend on advancing more treatments in strategically complementary indications and from there, building additional therapeutic areas from our fourth pillar to follow the first 3 pillars.

Let's take a moment to consider what we have accomplished. Our global commercial franchise and infrastructure is already built. We benefit from revenue generation from our marketed product. We have 2 strategically-overlapping pivotal stage programs with Brensocatib and ARIKAYCE frontline. We have a robust pipeline, a focused research effort to generate impactful medicines in new therapeutic areas, and a strong cash position. Insmed is on a path to realize this bright future for the benefit of our patients and our shareholders. All of this is overseen by a world-class leadership team with an impressive track record of executing commercial, clinical and regulatory pathways, who will now review where we stand in greater detail.

Let me start that process by turning the call over to Sara to walk through our financial results.

Thank you, Will. Good morning, everyone. A key priority for 2021 was maintaining financial strength, and we made important strides on this front. We bolstered our balance sheet and continued to benefit from the ARIKAYCE revenue stream, while exercising fiscal discipline. As a result, we are in a favorable position with balance sheet strength as we evaluate the many opportunities inherent in our existing portfolio.

Earlier today, we issued our detailed fourth quarter and full year financial results in a press release. All of those results are in line with our internal expectations. Let me highlight a few of our full year results for now. As reported this morning, we ended the year with $766.8 million in cash and cash equivalents and marketable securities. We believe this cash position will support our ongoing business into 2024.

There are 3 main variables that impact our cash position. First, revenue from our marketed products; second, how fully and broadly we choose to pursue the programs in our development pipeline; and third, how we resource launch readiness for several of these financial programs, including inventory build. We'll carefully consider these elements as we craft our plans going forward.

Now turning to the financials. Total net revenue for ARIKAYCE was $188.5 million for the full year 2021. As we look to each of our commercial regions, net revenue for 2021 was $159.5 million in the U.S.; $16 million in Japan; and $12.9 million in Europe and Rest of World. Notably, our U.S. revenue number for the full year 2021 demonstrates steady performance of the ARIKAYCE franchise over the prior year despite the rise and fall in infection and hospitalization rates in the shifting COVID landscape. We are encouraged by the overall improvement in the way in which people have adapted to the new realities presented by COVID around the globe. Consequently, these elements give us confidence that we will return to growth this year in all of the regions we are pursuing.

On a global basis, we anticipate seeing meaningful growth in ARIKAYCE revenue this year and are prepared to forecast at least 30% revenue growth year-over-year for 2022. Our gross to net in the U.S. for the full year 2021 were approximately 13.2%. Looking ahead at 2022, we anticipate gross to net in the U.S. to be in the mid-teens, consistent with our estimates from prior years. Recall that in the U.S., the first quarter is typically the toughest due to the deductible and co-pay resets for our Medicare patients that occur at the beginning of the year, resulting in the donut hole effect. As a result, we expect to see a similar trend to what we have historically experienced from fourth quarter to first quarter revenue levels.

Cost of product revenues for the full year 2021 was $44.2 million or 23% of revenues. This is consistent on a percentage basis with the cost of product revenues in the full year 2020.

Turning to our GAAP operating expenses. For the full year 2021, research and development expenses were $272.7 million and SG&A expenses were $234.3 million. In closing, Insmed has entered 2022 in a very strong capital position as we support the 4 pillars of our business. We intend to be responsible stewards of cash with the foresight to invest now to unlock the potential for candidates that may represent real improvements in healthcare for patients.

I'll now turn the call over to Martina for an update on our clinical development pipeline. Martina?

Thank you, Sara, and Good morning, everyone. 2021 marked another transformational year for Insmed with respect to our clinical trial work. Today, I'm excited to be able to share important updates around several of our programs and development.

Let's begin with Brensocatib, our DPP1 inhibitor, tied to the neutrophil-mediated diseases. I'm pleased to report that our Phase 3 ASPEN study for the potential treatment of bronchiectasis is now 50% enrolled, and we anticipate enrollment to be complete at approximately this time next year. Let me remind you that this trial is expected to enroll more than 1,600 patients at more than 400 clinical sites around the world. If there is one takeaway I can leave you with, it is this. For ASPEN to be halfway enrolled in just one year is an extraordinary achievement. And we believe this milestone demonstrate significant enthusiasm for the potential of Brensocatib for bronchiectasis patients, We are grateful to our investigators and to patients who have dedicated their time to this program at a very challenging time in regulatory medicine.

I'm also pleased to share that the first meeting of the Data and Safety Monitoring Board, or DSMB, took place at the end of last year, where it was recommended that the ASPEN trial continue as planned. Recall that bronchiectasis is a globally prevalent disease with no approved treatment and with over 1 million patients diagnosed worldwide, this represents an enormous opportunity for our compound. Furthermore, we believe COPD and asthma patients who may have undiagnosed bronchiectasis present additional market opportunities, given the comorbidity of these indications.

Let's now turn to the next area of Brensocatib development in cystic fibrosis. We are on track to release results this year or early 2023 from the Phase 2 PK/PD study, which will be instructive as to the appropriate dosing strength for CF patients. The trial is a single blind assessment of once-daily Brensocatib at 10 milligram, 25 milligram, and 40 milligram versus placebo in 36 patients with CF. Treatment duration is 28 days, and we will evaluate PK and safety data as well as reduction of NSP levels in sputum and blood, along with other exploratory spirometry measurements, such as FEV1. Following a review of safety and PK data, there is optionality to go to a 65 milligram dose, which may be warranted, given CF patients also have different metabolic profile versus non-CF patients. All toxicology work to support higher dose levels have been completed. The tremendous success of our Phase 2 [global] study highlighted the efficacy of DPP1 inhibition in treating bronchiectatic patients and suggest its potential role in treating CF patients. In addition, what excites us is the pathway of DPP1 inhibition for the treatment of many neutrophil-mediated diseases. And we have been doing significant work to explore how our compounds may benefit patients in other disease areas.

I'm excited to share with you today that we are moving Brensocatib into 2 new potential indications, Chronic Rhinosinusitis without nasal polyps or CRS and Hidradenitis Suppurativa or HS. These indications are an exciting new chapter in Brensocatib development, echoed by the enthusiasm from the deep bench of experts within Insmed, who have experience in these disease states. We see clear scientific rationale supporting the potential role of Brensocatib in pursuing these indications. As we are targeting the neutrophilic activity in the inflammatory pathway of disease, we believe that DPP1 inhibition leading to a reduction of NSP level may be able to interrupt the inflammatory components of these diseases.

First, it's important to distinguish CRS without nasal polyps, which we are targeting from CRS with nasal polyps. Both can be severe diseases, but with CRS without polyps, we generally see more neutrophil recruitment in the inflammatory process, aligning with the mechanism of action demonstrated by Brensocatib. There are currently no approved therapies for patients with CRS without nasal polyps, which is the most common type of Rhinosinusitis. CRS without nasal polyps is characterized by chronic inflammation and fibrosis of the mucus membranes inside the sinuses. The most common symptom include nasal obstruction, decreased sense of smell and facial pain. Patients with CRS also report lower quality of life measures, impacting bodily pain, general health, physical and social functioning and the disease is associated with increased rates of depression. Currently, the only available treatment option for patients with CRS without polyps are corticosteroids, antibiotics or endoscopic procedures. These endoscopic surgeries may have to be repeated. We are targeting patients at the severe end of the disease spectrum for whom surgery does not work. All of these signals the need -- an urgent need for a safe oral therapy for these patients.

Let's now turn to HS. HS is a chronic inflammatory skin disorder characterized by painful, inflamed and small lesions, affecting hair follicle, often in the armpits, groin and skinfolds. The clinical course is variable, ranging from relatively mild disease characterized by the recurrent appearance of inflamed lesions and nodules to severe cases with deep abscesses, draining fistulas and severe scars. Patient-reported quality of life measures indicate a high psychosocial impact from the disease with increased rates of anxiety and depression. We are targeting the moderate to severe end of the disease spectrum. There is only one approved therapy for HS, which doesn't work for all patients. And given the complexity of the disease, patients can require multiple treatment and sometimes surgery to maintain control of the disease. We have seen enthusiasm among healthcare professionals for investigational therapies to help identify new effective treatment options for both HS and CRS.

Let me take a moment to walk through the study designs. Our current plan is to move CRS into the clinic in a Phase 2 study over a 24-week treatment period, exploring Brensocatib at 10 and 40 milligram versus placebo, followed by 4 weeks of therapy with the primary endpoint of change in an established measure of total symptom score.

Let's now turn to the trial design in HS. We anticipate that our Phase 2 trial in HS will span a 16-week treatment period, exploring 10 and 40 milligram of Brensocatib versus placebo, followed by a 36-week open-label extension period. The primary endpoint will be percentage of subjects achieving Hidradenitis Suppurativa clinical response at week 16.

All of this aligns with our broader strategy of building a portfolio around the DPP1 inhibition pathway to target neutrophil-mediated diseases. We anticipate advancing one of these new indications into the clinic this year, and we will have more to say about our overall progress with Brensocatib in all indications in the next few quarters.

Let's now turn to the ARIKAYCE frontline program. I am excited to report that the ARISE study is now 50% enrolled, and we anticipate reaching enrollment completion this year with topline data from ARISE in the first half of 2023. We also anticipate ENCORE to be fully enrolled in 2023. As a reminder, data from ARISE will inform and allow us to finalize the PRO utilized in the ENCORE trial. These timelines are consistent with what we have seen in our previous NTM trial, reaffirming that enrollment of NTM trials typically proceeds at a slow pace. As was the case in our previous trial, positive sputum cultures are not always present at the time of patient screening, and it is not surprising to see screen failure rates surpass 40%. Recall that ARISE preferentially enrolled over ENCORE with the randomization of 221 and once ARISE is fully enrolled, we anticipate enrollment in the ENCORE study to accelerate.

As additional study sites come online, we also anticipate this will help drive enrollment momentum in ENCORE. In addition, ENCORE is a more attractive study from a patient recruitment perspective because it provides an uninterrupted treatment cycle, allowing patients to stay on therapy for a full 12 months versus 6 months for ARISE. This is a relevant factor for patients and physicians as they evaluate their participation in these clinical trials. We look forward to maintaining our enrollment momentum in both of these studies, and we'll update you on our progress.

I'll now turn to TPIP. TPIP is our treprostinil prodrug in Phase 2 development for both PAH and PH-ILD. This is an exciting opportunity as we believe that our compound could unlock the full potential of the prostanoid pathway to benefit patients with certain rare pulmonary disorders. Let me take a moment to walk you through our Phase 2 trial design. The first study to discuss is the randomized double-blind placebo-controlled Phase 2b study that will affect the efficacy, safety and PK of TPIP in patients with PAH over a 16-week treatment period. Target enrollment in this study is approximately 100 patients. Patients will be dosed once daily and each patient will be up-titrated to his or her individual maximum tolerated dose. The primary measure is the change from baseline in pulmonary vascular resistance or PVR at week 16, and the key secondary measure will evaluate the impact of TPIP on 6-minute walk distance at various time points. As planned, site initiation for the Phase 2b trial in PAH patients began late last year. We will update you on the relevant progress in the coming quarters.

The second study to discuss is the randomized double-blind placebo-controlled Phase 2 trial in PH-ILD, which will assess the safety and tolerability of TPIP over 16 weeks. Target enrollment is 32 patients. As with the study in PAH, patients will be dosed once daily and each patient will be up-titrated to his or her maximum tolerated dose. Other key endpoints will include TPIP PK profile as well as various exploratory efficacy measures, including effects on 6-minute walk distance. We think TPIP may be well positioned for this indication by the way of inhaled route of administration which delivers vasal dilation to the ventilated areas of the lung. Systemically-administered therapies, on the other hand, can lead to vasal dilation in the areas of the lung that due to fibrosis are not ventilated, leading to a ventilation perfusing mismatch. The TPIP route of delivery is intended to mitigate this problem with a potentially more favorable side effect profile as well as longer lung residency time versus inhaled (inaudible). Site initiation for the Phase 2 trial in PH-ILD patients is currently underway, and we look forward to keeping you apprised of our progress.

Finally, the ongoing Phase 2a 24-hour right-heart catheterization study, evaluating PDR and PAH patients continues to look for volunteers. And we're hopeful that with Omicron receding, we will be successful in identifying volunteers and advancing enrollment. While this study is not rate limiting to the other Phase 2 trials we have discussed, we are excited by the potential the results could suggest for our TPIP program and look forward to providing results from patients in this study as we collect data over the course of this year.

I'd like to close by recognizing the significant and growing excitement behind our fourth pillar, translational medicine. This pillar is led by multiple teams and contains several exciting technology programs running in parallel, some of which are complementary to one another and others that are standalone therapies targeting different and unrelated conditions. We envision that some programs within these 4 pillars may act as a platform capability, for example, the potential deimmunization of capsids and gene therapy. We anticipate that translational medicine will serve as the IND engine for Insmed's future, thereby addressing the question of what may follow the anticipated success of our first 3 pillars. We hope to make significant progress from this effort in 2022, culminating in the filing of an IND in a new nonpulmonary indication by the end of the year. In parallel to this program, there are several other components of our fourth pillar, and we envision a detailed research day in the second half of this year, at which time we anticipate sharing preclinical data. While this represents an important pillar for our future, I continue to work closely with Sara to ensure capital allocation to these areas remains measured and is deployed only with successful data along the way.

In summary, Insmed realized several major clinical achievements over the past year. 2022 is poised to be a critical year of execution across our clinical operations, and we look forward to delivering on the catalysts we've outlined today.

With that, let me turn the call over to Roger to discuss some key operational updates. Roger?

Thank you, Martina, and Good morning, everyone. From an operational standpoint, there are 2 main areas I want to focus on today. I'll start with the commercial operations surrounding our first pillar, ARIKAYCE. From there, I'll turn to the expansion of our second pillar, Brensocatib and the additional clinical indications we have decided to target.

For our ARIKAYCE franchise, Insmed's commercial operations continued to perform extremely well over the course of 2021. Last year ushered in a new era for ARIKAYCE, which is now launched in the U.S., Europe and Japan. I'd like to take a moment to walk you through our recent progress in each of these regions.

Let's begin with the U.S. The ARIKAYCE franchise has remained resilient throughout the ongoing pandemic, underscored by a solid fourth quarter performance despite the arrival of the Omicron surges that rapidly swept the country beginning late last year. We continue to see reasonable variability across the U.S., but some area is more impacted by COVID than others. In particular, we have noted the impact of Omicron on the availability of workers in the medical setting, and we are all keenly aware of the pressure on healthcare professionals, particularly pulmonologists, infectious disease doctors and respiratory therapists. However, despite these challenges, we believe we have the resources to achieve growth as our therapeutic specialists continue to have positive interactions with physicians treating refractory NTM patients. Although COVID has impacted physicians' ability to see NTM patients, we also believe that the pandemic has brought to light a larger focus on pulmonary disease and potentially a higher index of suspicion for refractory NTM. These factors, combined with our ability to adapt to the new circumstances of COVID create potential for growth in the U.S. and our international markets.

Let's drill down into our ex U.S. commercial efforts. Beginning with Japan, where we are extremely pleased with the launch progress thus far. As a reminder, the launch in Japan began in July of last year. We believe that the opportunity in this market is significant and that in terms of revenue, Japan will be the second largest market for ARIKAYCE after the U.S. Recall that for the first year of market availability in Japan, all drugs are restricted to a 2-week dispensing limit. Practically, this requires the patient to return to their physician's office every 2 weeks to receive their prescription. This 2-week restriction also impacts affordability for patients. Monthly patient copays are capped in Japan. So under the current restriction, a patient would receive a maximum of one month's supply for their copayment. Once this restriction is lifted in June, patients will be able to receive up to 3 months of ARIKAYCE for the same copayment.

In addition, the Japanese society for tuberculosis and non-tuberculosis mycobacterium published guidelines on the appropriate use of ARIKAYCE, recommending usage for patients who do not achieve culture conversion with a multidrug regimen over 6 months. The guidelines also offer advice on managing adverse events. We see this as a positive development that may help physicians better understand the key considerations as they think about prescribing ARIKAYCE to their patients and managing the side effect profile. We are extremely excited about the opportunity in Japan and look forward to updating you on our progress.

I'll now turn to Europe. We anticipate the addressable market is smaller than those in the U.S. and Japan. However, we have made excellent progress with physicians. And as reimbursement occurs in additional countries, we anticipate Europe will be a meaningful revenue contributor to the overall franchise. As we work to drive growth in this market, we continue to believe that the literature estimation of 1,400 diagnosed refractory MAC patients in Europe may be understated. ARIKAYCE is currently available under our free pricing program in Germany and the prices renegotiated after the first year on the market. We await a final pricing decision in Germany in the first half of this year. With the product also available and reimbursed in the Netherlands, Wales and Scotland, we now turn our attention to England, France and Italy as we await reimbursement decisions from those territories throughout this year.

We have confidence in the future growth from each of our 3 regions where ARIKAYCE is available. As we continue to learn about and adapt to the realities of COVID, we believe we have the resources for our commercial operations to succeed in this challenging environment.

I'd like to now turn to our second pillar, Brensocatib, and the market opportunity in our newly announced indications, CRS and HS. CRS without nasal polyps represents a significant opportunity. There are approximately 33 million patients diagnosed with CRS in the U.S. Of those patients, approximately 26 million patients have CRS without nasal polyps. We are targeting the severe end of the disease spectrum, which represents a smaller, though, still substantial portion of the overall CRS without nasal polyps market. We believe a good proxy for severe disease are those patients who require surgical intervention. Each year in the U.S., approximately 155,000 patients undergo surgery for CRS without nasal polyps. Of those, approximately 15% or 23,000 patients require revision or repeat surgery.

We consider those patients undergoing repeat surgical intervention to be most severe. To be clear, these are annual incidence numbers and pending supportive clinical data, we expect these patients to take Brensocatib chronically. As Martina mentioned, there are currently no approved treatments for this indication. If we are able to demonstrate clinically meaningful impacts on this disease, we believe physicians may be inclined to try a well-tolerated effective therapy prior to recommending either initial or repeat surgery. We believe patients may also prefer a well-tolerated effective oral medication to surgical intervention.

With HS, we estimate there are approximately 300,000 patients in the U.S. Approximately 1/3 of these patients or about 100,000 have moderate to severe disease. We will be targeting the more severe patient group with Brensocatib. HUMIRA is currently the only approved treatment for HS patients, and we believe that Brensocatib, a well-tolerated oral therapy with an attractive safety profile, will be a welcome addition to the treatment armamentarium. We anticipate Brensocatib will launch in bronchiectasis first. We believe this indication may support attractive pricing if we are able to show clinically meaningful impacts on this disease. As we selected additional diseases to target, we wanted to ensure that the pricing was sustainable, assuming we are also able to show clinically meaningful results. We believe the presence of approved biologics in both severe CRS with nasal polyps and HS validates the potential of these disease states to support strong pricing as well.

When we take a step back and look at the overall picture of our Brensocatib-targeted indications, bronchiectasis, cystic fibrosis, CRS and HS, we see a pathway to what we believe is a very sizable market opportunity.

In summary, the operational outlook at Insmed is strong. I'm proud of the team that has helped us execute on our milestones during a productive 2021. I look forward to what I believe will be another transformational year for the company.

I'll now turn the call back to Will.

Thank you, Roger. I'd like to close out my remarks by emphasizing Insmed's position of strength, backed by a seasoned leadership team, a reliable and growing commercial franchise, a diverse pipeline of early-to-late-stage assets and a solid cash position. We have the elements we need to advance this company to the next level of growth. I believe Insmed can reach our goal of becoming one of the next great biotechnology companies. We will work to execute against the objectives we have laid out for you today for the benefit of our patients and our shareholders.

I'd like to acknowledge the hard work from the entire Insmed team, and I would like to extend my gratitude to the patients and caregivers who participate in our clinical studies.

And with that, I'd like to open the call to questions. Operator, can we take the first question, please?

(Operator Instructions) And the first question comes from Jessica Fye from J.P. Morgan.

For the '22 revenue guidance pointing to sales of at least $245 million for ARIKAYCE this year, I know you talked about growth in all regions, but can you help us think about the contribution from each geography that underpins that lower? And maybe talk about the extent to which this might be conservative or how much conservatism you kind of reflect in that number.

Yes, sure. I appreciate that question. Look, I think we've all experienced the uncertainty that surround the pandemic's ebb and flow. What we tried to do with this forecast was to put out there a number that we feel very good about in terms of its defensibility despite whatever may happen in the pandemic market. So I think there -- certainly, the first quarter, as you know, is always the most challenging for the rare disease products, but we see a positive year across the board. I don't know, Sara, if you want to add anything to that.

Yes. No, thanks, Jess, for the question. Maybe just a couple of other things to add. We're obviously very encouraged and excited to be able to share at least a 30% growth. That's obviously a meaningful growth year-over-year from '21 to '22. As Will mentioned, Q1 is always sort of the most challenging quarter in the U.S. due to the donut hole reset and all those good things that we see across high-price rare disease products. And as the year progresses, in Japan, we expect to be a meaningful contributor, as Roger mentioned, the second largest contributor in our 3 regions with that June time point as the lift of the 2-week prescription, which really helps patients from a copay perspective. So hopefully, that gives you a little more color.

Great. And second question on TPIP. For that Phase 2b in PAH, what background therapies are allowed and what do you expect the mix of single and dual agent background meds to be? And I know you're expecting better sort of coverage with TPIP relative to Tyvaso, but do you expect the PDR data in the Phase 2b to compare well to Tyvaso?

So I'll ask Martina maybe to take that question.

Yes. So we expect that TPIP -- what we've seen from TPIP in the healthy volunteer study is that we don't go up to such a high Cmax. We have a larger and a prolonged exposure on the AUC perspective. We've seen the key half-life in this study going out even with our lowest dose to 24, 36 and even to 48 hours. So we expect that we will have a good impact on the PDR. And from the PK profile, that's what we saw in the healthy volunteer study, there's no reason to believe that, that will be significantly different in the PAH patients.

Our next question comes from Jeff Hung from Morgan Stanley.

This is [Melina] on for Jeff. Can you talk a little bit more about for Brensocatib, the CRS and HS indications? What are the determining factors to advance those indications into the clinic this year? Is there any specific data that you're waiting on for each indication?

Yes. No, I appreciate that. I would say that we went through a pretty significant process and maybe, Roger, do you want to talk a little bit about that and Martina, I'll ask you to comment on the logic scientifically.

Yes, sure. Thanks, Will. So we actually did a pretty exhaustive process. We're working with some external partners. We screened diseases, and we actually ended up screening about 150 neutrophil-mediated diseases. Our next step as we sort of narrowed that down was to look at the disease states that were primarily driven by neutrophil involvement and we tidied that list down to about a little more than 60 diseases. From there, we then looked at the epi and we wanted to understand the size of the opportunity, we looked at the burden of the disease and narrowed that final list down. And then as we selected CRS and HS, we really focused on, #1, the science, so obviously driven by neutrophil involvement, the unmet need of the patients and importantly, the competitive intensity, which is somewhat related to the unmet need of the patients. But in HS, there's only one approved therapy, as we mentioned, which is HUMIRA. And in CRS without nasal polyps, which is the neutrophilic phenotype of the disease, there are no approved therapies, and that's counter to the CRS with nasal polyps, where there's a number of biologics, Dupixent, Nucala, for example, that are targeting that portion of the population. So the competitive intensity is really attractive to us.

And then finally, as I mentioned in my prepared comments, as we looked at pricing, we expected that Brensocatib will be supported in bronchiectasis with some attractive pricing. And we wanted to make sure that across our indications that we felt that payers would reimburse us at that same sustainable attractive pricing. And we think across the disease states with bronchiectasis, CF, CRS and HS that we will be able to achieve that. So we feel very good about these disease states where we're targeting now and the impact that we're going to bring to patients.

Yes. And about scientific rationale. So there are no really good preclinical models for both of these diseases, but they are both associated with neutrophil inflammation. And if you look at CRS without nasal polyps, neutrophils play a key role in the fibrotic remodeling of the mucus membrane inside the sinuses. This remodeling leads over time to tissue damage and worsening and worsening of that disease. So from -- both in CRS and in HS, the neutrophil component is an important driver. And in HS, the neutrophils are prominent and you see them in the effective skin lesions. What you also see in this effective skin lesions is that an uncontrolled release of these NSPs leads to a high contribution and a presence of [net]. And there is correlation between this net formation and the severity of the disease. So for both of them, Brensocatib attracts what is the effective cells. And that is the neutrophilic activity through the TPP1 inhibition.

And I would just say, we are moving forward with all speed in both of these indications. You saw draft designs of clinical trials in the slides today and the discussion that Martina provided. Those are going to continue to be refined. We've had very good KOL interactions, they're very strongly supportive of pursuing these. The only thing that holds us back from doing perhaps even more of what Roger was indicating is resource and thinking carefully about balancing how many eggs to put in this particular basket. We have excellent data in bronchiectasis. We have a very strong scientific rationale for these next 3 indications, as you've just heard. And I think what this really represents is the tip of the iceberg for DPP1 inhibition in neutrophil-mediated diseases. We have really unlocked a pathway here. And I think the potential for Brensocatib to get even bigger than it already is, is very real, and that puts us into a pretty enticing blockbuster category. So lots of work to be done and validation to be provided behind that ambition, but I think the more we look at this and the more science we study, the more excited we get.

Great. And if I could just ask one more quick one on the TPIP program. I think the Phase 2a data was pushed back originally from the first half this year to just 2022. Have you gotten any sense from prospective participants what they need to see in order to be willing to go into the ICU, particularly during these winter months when COVID rates may be higher?

Yes. This is a frustrating one for all of us. Look, the Phase 2a study has been in design and out there for some time. The big challenge here is that, as far as we know, there is no precedent for this study, doing a right-heart catheterization on somebody that lasts more than about 4 hours, we're not aware of studies that have ever done that. We're proposing to do it for 24 hours. And what's interesting about that is that the key opinion leaders who have opened their centers to pursue this are enthusiastic about doing so. They really think this data is going to derisk this program's potential very substantially. So we are excited to get the data. Finding someone to volunteer who has PAH in an advanced state, and is willing to have a right-heart catheterization for 24 hours, while they sit in an ICU surrounded by COVID-infected patients, that's a very high bar.

I think we probably underestimated how severe an ask that was. But we're pursuing it. We have identified some patients by name. They will indicate at times that they want to come in and then they get a little bit nervous. So we're trying to work as productively as we can and as Omicron recedes, I think we have a very good chance of getting those patients. That's why we've sort of said, look, to get all the data, it may take a little bit longer. But importantly, we plan to get the data. And once we get it, we will share it and that could be at any time across the year.

Our next question comes from Ritu Baral from Cowen.

I wanted to ask about ASPEN and what you're seeing so far. Have you been looking at event rates -- blended event rate for exacerbations in ASPEN? How are they comparing to expectations? And frankly, should we be thinking about any COVID impact on exacerbation rates in this population, up down with rates and whether this seems to be happening more with COVID in this population? If you could just help frame that.

Yes. So what we're doing is we're applying the cash and looking at the event rate on a weekly basis and it's what we're seeing matching our assumptions. So from that perspective, what we're seeing is matching our assumptions at this time. When it comes to COVID, there is -- that is an additional aspect in every respiratory study right now. So we also know which patients, how many patients have COVID. So remember, all of these is in a blinded mesh in a blinded way. We don't see the individual. But we have a clear view of what is the patient population. Do we see anything that deviates right now from our assumptions? And at this point in time, we see what we had estimated.

Similar to what we saw in WILLOW.

And similar to what we saw in WILLOW.

So we're in a great spot right now, Ritu. I mean, this trial is not only enrolling quickly, but the monitoring that Martina is describing has gone remarkably well, and that is something that she said, we're tracking on a weekly basis. So we are all over this.

Got it. And then a question for Roger, just on the new Brenso indications. As you think about that severe CRS population, you think about HS, who are the treating physicians that you think will ultimately be commercially targeted? Are they like ENTs and then specific derms or are they sort of more broad than how I might be thinking about it?

Yes. Thanks, Ritu. So you're right. For the CRS, it's the ENTs. So these would be the folks that will primarily be performing the surgeries. So we will be targeting the ENTs. And to be honest, we'll need to figure out, there's about 10,000 to 12,000 ENTs in the U.S., approximately the same number for derms. We'll need to segment that population and do the work to figure out who we're going to be reaching out to address these diseases and see who are the experts in that field. But yes, ENTs and then with the derms, we'll do the same process, right about 10,000 to 12,000. We'll take a look at probably a really good indicator as you see a dermatologist is using HUMIRA, that's going to give you a really good lead as to who you need to be talking about to bring Brenso to them. So we'll update you later with more specifics about that, but that -- those are the specialists that we're focusing on.

Our next question comes from Judah Frommer from Credit Suisse.

First, just a quick follow-up on ASPEN. You mentioned kind of the 50% enrollment versus internal projections. Did those change at any time tied to COVID or is that kind of an initial projection that stuck? And then you did talk about enrollment timelines. Does that kind of foretell or read out in kind of the mid-2024 range?

Well, these are consistent. I mean, the internal projections were set after COVID was underway, as you might recall. So we certainly contemplated that. I would say, we took a pretty aggressive line on what we were trying to accomplish here. As we described early on, we were going to really resource this trial and give it our best efforts and I would say even in the context of those ambitions, this has outperformed. And I think what we're trying to put our finger on today is that a part of that is coming from the enthusiasm that surrounds the arrival of this potential medicine described by someone at the American Thoracic Society as potentially the holy grail of pulmonary medicine. So there's real palpable enthusiasm for this program out there, and that's affecting enrollment. I think the other question was timing for data. So this is a 13-month study, 12 months on drug and then one month off drug. So you can run the math off of whenever we're finally fully enrolled, it will be roughly 13 months plus the time to lock the database and release it in topline form. So we say approximately this time next year, we should be fully enrolled.

Okay. That's helpful. And then there were a couple of comments just around allocation priorities, upfront in the presentation, and then kind of toward the end you're not allocating -- over-allocating to that pillar 4. Can you give us a little bit more color around priorities for cash allocation? Are there specific areas you're thinking about, that you may need more whether it's accelerating ENCORE enrollment or maybe to allocate sales force for pushing these new brands out, indications? Just any color would be helpful.

Well, the first thing I would say is, as we think about the 4 pillars, obviously, the largest spend is on the first 2 at the moment where we have pivotal trials that are global in reach and large in scope. TPIP probably follows behind that. And then the fourth pillar punches way above its weight with very little resource because it's an earlier stage. And importantly, the medicines that are being produced there, they prove to be effective, have a potentially shorter pathway through the regulatory maze, because they can be highly impactful to very severe patients. So we have a long way to go to accomplish that, but I'm excited about the prospects of that. and we'll have more to say about the fourth pillar in detail in the second half of this year when we do an R&D Day. Hopefully, you noticed on the slide where we've enumerated 9 different programs to give some sense for how productive this engine already is and where it could lead us as a company is very exciting. I don't know, Sara, if you want to talk about guidance for any of those different spends and how we're thinking about it.

Yes, sure. As Will mentioned, our largest focus from a capital prioritization perspective is around the ARIKAYCE and Brenso programs. And so as we think about ARISE, ASPEN, ENCORE, we are resourcing those programs and ensuring those programs are as successful as they could be. And so as you see the success that we've had with ASPEN, over 50% enrolled, just a degree of that study, just as a reminder, that means it's over 800 patients that we've enrolled in about a year. That's pretty remarkable as you think about comparator trials. So we are resourcing these programs appropriately. And Martina and I stay in close contact around prioritizations around all 4 pillars. Translational medicine, it's an immaterial spend for the amount of answers and questions we're going to be able to get out of that pillar.

Our next question comes from Joseph Schwartz from SVB Leerink.

I'm Joori dialing in for Joe. First is on pricing in Japan. Does ARIKAYCE get renegotiated after the first year in Japan?

Yes. Thanks for the question. There will be pricing adjustments for ARIKAYCE in Japan. We're not anticipating it from the first year, but there are -- I think it's every 2 years that we are anticipating that there will be pricing adjustments potentially in Japan. It's not a given, but we're anticipating that there may be those renegotiations every couple of years.

Okay. Great. And then if I could just squeeze one in. For ARISE, I believe the first patient was dosed last -- late December and it's like about 14 months to get 50% enrollment. Curious what give confidence that the ramp-up of enrollment can happen in the next 10 months or so of the year that's remaining? And are you planning to have more sites? Or are you detecting more interest? Any color on that would be helpful.

Yes. As you've heard in Martina's comments, one of the challenges of NTM studies is just that these patients are very skittish, particularly, in the global pandemic. We've been through this before with 2 other studies in the refractory population, both Phase 2 and Phase 3. So we're accustomed to it. If you look across this disease state, this is sort of the typical approach. What's interesting is that notwithstanding getting them in the clinical setting, the commercial opportunity that gets represented by this, the uptake is quite substantial. So we're excited to get to the other side of ARISE and ENCORE because of what we think it's going to represent. There are a lot of patients out there that are going to benefit from this.

It is also important to remember that we're asking in the ARISE study for patients to take the drug for 6 months and then one month off and that is not what guidelines call for. So it's a little bit of a higher hurdle to get them to step into ARISE. It's one of the reasons why we think ENCORE is going to enroll faster. There are several countries that are now participating in ARISE that are participating in ENCORE. And so that will also add additional sites and enrollment horsepower to ENCORE once ARISE is completed. But we know what the screening is. We know what the front end of the funnel is, if you will, and that's where our confidence comes from that we think we'll be able to complete this in due time.

Our next question comes from Stephen Willey from Stifel.

Maybe just to follow up on the last question. I think there was a comment that Martina made around screen failure rate that you guys were seeing in, I believe, it's ARISE or ENCORE being, I think, somewhere north of 40%. And I was just wondering if you could maybe kind of provide some commentary around what seems to be driving that specifically and whether or not that's in line with prior studies that you've done in this disease setting, I guess, specifically (technical difficulty)

Yes. The first thing to remember is that prior studies that we've done, the CONVERT study was in a refractory population. So those are already patients that are diagnosed, and they haven't responded to treatment. So you would get this positive sputum cultures already when patients come to physicians and they are at the site. In the frontline indication, so these are naive patients, and very often for these patients to produce sputum is already hard. Then to actually get a positive sputum culture is the next hurdle. And in addition, today, what you often have to do with this patient is to actually help them to induce sputum production. So there is an element of that that sites don't do this today, that's related to the COVID guidance that they all have, and then it takes a significant amount of time until you really get to a culture that is positive. And we want to ensure that we have a high-quality culture and we have the right patients. You don't want patients in the study who just have colonization, but they don't really have a good positive culture. So that's a part of that.

Now it's a different environment when you're in a study situation that what you would be having in normal -- in the normal clinical practice setting, there is a higher hurdle on that. And then part of it, we've seen this higher screen failure rates often because it's very hard for them to produce it. They just can't come up with it, then you have to wait until you get that positive culture to make sure we have the right patients in this study. That's also a very big driver for the screen failure rates as well.

Okay. That's helpful. And then, I guess, just with respect to the Phase 2a study for Brensocatib in CF, I think prior guidance maybe suggested that was going to be a '22 disclosure. I think you're now maybe talking early '23, maybe it's just semantics. But is there anything rate limiting there in terms of enrollment? Is that COVID-related? Is that you pushing dose escalation a little bit higher than you perhaps were before?

No, that doesn't really -- that hasn't really changed. All we're really trying to indicate is that, at this stage, it's hard to predict exactly what the enrollment path will be. There's no new information that would redirect the timing of that. We'll update you throughout the year as we see what the progress is. I think if we've added that extra little bit of space, it's in the event that we were to go up to 65 milligrams, for example. Martina talked about the 3 doses we're currently targeting. Depending on how patients respond, we may need to go to 65 milligrams. And so to do that, it might take a little bit longer. That's all that's really playing out there.

Our next question comes from Liisa Bayko from Evercore.

I just wanted to understand a little bit more about the dynamics of how you're thinking about ARIKAYCE. You're kind of well into the quarter already, for the first quarter. Any updates on sort of trends you're seeing? And then as you think about guidance for next year, can you give us any color on what -- is the growth coming primarily ex-U.S., U.S.? Maybe you can give us some breakdown of how you're thinking about the 30% growth across the different regions.

Sure. Happy to. Thanks, Liisa, for the question. So we're excited and encouraged to be able to reinstate our revenue guidance first time in 2 years that we've been coming out with revenue guidance with a 30% year-over-year growth is substantial growth. We anticipate that we will see growth from all 3 of our regions. As I mentioned earlier in the prepared remarks, Q1 is always the toughest in the U.S. due to the donut hole reset and all of those good things, as you've historically seen throughout our Q1 and as Roger mentioned in his remarks, around sort of the nuances in the Japan market on the 2-week restriction being lifted in the June timeframe. So some nuances as you think about the different regions, but we do expect to see growth in all 3 of our regions. And we have, as a global society, gotten to a place where we understand COVID and folks are learning how to live in this new environment. So hopefully, that gives you a little more color.

Maybe I'll just add in a couple of comments because I think what we're seeing and as Sara has said, first quarter is always a tough quarter for the U.S. with the copays and the deductible resets and so forth. But what we're really encouraged, if we look at Omicron and look what's happening with COVID, we got -- the whole country got hit with that at various times. And we're seeing -- it's still a regional impact, but we're seeing trends in the Northeast where hospitalization is just plummeting in the U.S. And we're seeing some specific areas that we -- where we -- our sales reps are able to get back in front of customers and have more in-person calls. And we think that that's really important. We know the pulmonologists have been particularly hit hard in IDs with the whole COVID situation. And as we see that start to subside and, knock on wood, we're all hoping we're getting to the other side of this, we think we'll see patients coming back in. We think a lot of these pulmonologists are going to be really focused on respiratory health. Everybody is focused on long COVID, understanding the impact of that disease. I think that's going to drive index suspicion for NTM and for other comorbidities and focusing on lung health. So we're really optimistic for growth across our regions.

We've got a number of catalysts in Europe with the reimbursement decisions. In Japan, we're really thrilled with how the launch has progressed in Japan. We'll watch -- watching what's happening with Omicron there as well. I would say that it's interesting, the data I have just seen showed that actually it seems to be hitting their population harder than it's hit the U.S. and Europe. The deaths that they've actually recorded in Japan were higher than what they saw in the summer, which was the Delta variant. So it's had a really pretty profound impact. I mean, there's some theories floating around, I think the boosted population in Japan is about 9% was the data that I heard, which is significantly less than what we've seen in Western countries. So -- but if we see the same pattern there, where you see it peaking and then receding dramatically, I think that we'll continue that launch at pace. And we have the catalyst of the Japanese Society providing that input and a recommendation for ARIKAYCE, the copay dynamic that will come with the 2-week restriction being lifted in June. We're really optimistic that we'll drive that growth in Japan as well. So across our regions, we're really optimistic, and that's reflected in what we tried to lay out there as our guidance.

Okay. Great. And then just on the -- Japan and in Europe, does this reflect the kind of 2021 numbers you provided? Is that mostly end user demand? Or is there any kind of channel fill there? Anything about -- because I know you kind of, at least in Japan, launched fairly recently, and I'm just trying to understand if there is this channel fill dynamic or that's really reflecting end user demand? And then for Europe, how do you get to a point where you have a better sense of what the patient number is? is it just like -- just because -- where you're at already in terms of the share you seem to be getting? It's already pretty substantial. I'm just wondering when you might have a better handle on actually how many patients there are available out there.

Yes. So we don't see that -- I think your first question was really, are we seeing stocking, right? So are we putting products into the channel. And we work with wholesalers in Japan, and this is reflecting user demand. So we sell the devices directly into the hospitals and ARIKAYCE goes to the wholesalers and to the hospitals. But because it's a fairly expensive product, you don't see a lot of stocking and carrying of that inventory. And in Europe, it's the same phenomenon, right? So we don't have that kind of phenomenon occurring. And what was the second question? Oh, the 1,400 patients, yes, sorry, thanks. Yes, look, I think we're loath to put out estimates that aren't supported by the literature, right? So I think everything we've looked at and as we -- and all the literature that's available point to those 1,400 refractory patients. We're really skeptical about that. We think it is a larger number for a number of reasons. The KOLs see these patients. They are anxious for the therapy.

As you mentioned, we're actually seeing some substantial revenue already from Europe without reimbursement, and we had the named patient program in place there. And so we think, over time, if you think about the risk factors for NTM, it's an elderly population. If you've got a history of smoking, its proximity to the water, all of those things are true in Europe as they are in the U.S. and Japan. So we think that the population may be understated in the literature. We don't have anything hard that we can point to around that. So we're conservative as we think about what we represent as the market might look like. But over time, we'll see that and we'll validate that. It will take longer for us to grow that market. There is a sort of more of a medical center of excellence, kind of an approach in Europe. But we think, with an approved therapy that's reimbursed, you'll see these patients be treated. You'll see them identified, and we'll see that opportunity to grow over time.

(Operator Instructions) Our next question comes from Jennifer Kim from Cantor.

Maybe starting with TPIP. In terms of timing for the Phase 2b trial, clinical trials has an estimated primary completion date of February 2024. And I know that's not the most reliable indicator. But I'm wondering, based on how enrollment has moved for that asset in the Phase 2a and the enrollment we've seen with other assets as well, is it fair to call that an aggressive timeline? Or is it too early to say for now?

I think it's too early to say what the timeline will be for that. That's why we didn't provide it in the brief and the spoken comments. What I would draw your attention to is that I think it's very different to be enrolling for this Phase 2b trial and the Phase 2 PH-ILD trial than it is the 2a trial. The 2a is really blocked by the onerous nature of the protocol where a patient has to have the right-heart cath for 24 hours. And so getting volunteers to go into that is challenging. Both of these Phase 2 trials, the Phase 2b in PAH and the Phase 2 in PH-ILD are following a fairly standard protocol approach. And so there's good precedent out there for enrolling patients in this kind of trial. The patients are accustomed to it. It's just a question of executing it, and I think the team has proven its worth in that regard. So I'm confident that they will deliver the enrollment in as rapid a time as quality will allow.

Okay. Great. And maybe one quick second question. For ARIKAYCE in Japan, you've talked about the 2-week prescription limit and the COVID impact as, I guess, the 2 things sort of restricting growth in 2022. And I'm wondering broadly what level of impact do each of these things have in 2022 in your mind? I'm just thinking about how we should start to think about 2023 as those factors go away.

Yes. Thanks. It's -- so first of all, I just want to say, I think the Japanese team has done an amazing job in launching ARIKAYCE, and you've seen the sales that [you] reported from last year in just a little bit more than 6 months -- less than 6 months of sales. And so we expect this trajectory to continue at pace. I think the impact of COVID and Omicron is real. We are having trouble with accessing physicians in person because they're being pulled to their hospital duties, take care of these patients. And the government is restricting hospital beds. So even if they're unused, which if you look at the numbers, there are probably not a lot of unused right now, but they're restricting hospital beds and reserving them for COVID patients. And recall, we had talked about earlier, there's a predication in Japan for physicians to start ARIKAYCE patients in the hospital for at least a couple of days so they can monitor them, make sure they're tolerating the product, okay. So we think that it's hopefully a first quarter phenomenon, right? So where we're seeing that Omicron will peak, we'll get to the other side of this and be able to return to some sense of normalcy.

The 2-week prescription, I think is a real issue. I think what we've seen is the early adoption has been for those patients who've been waiting for ARIKAYCE have the more severe patients and are willing to look past that copay burden for them to start. I think once that's lifted, we'll see a pretty strong reaction both from the physicians in prescribing for the patients because, of course, they're sensitive to the economic burden of the patient as it's mostly elderly, and also from the patient, they will be able to receive up to 3 months of medicine for the same copay that they currently receive up to one month right now. So I think we're really excited about and have confidence in the Japanese launch. I think we've got a couple of catalysts and the second half, I think, will be a stronger uptick because of those factors.

(Operator Instructions) The next question comes from Anita Dushyanth from Berenberg.

Thank you for the update and guidance and also congrats on the results. I had a question, sorry if I missed this in your commentary. As for your application of Brenso to CRS and HS, would you be taking both -- investigating that in both of those indications this year? Or is there a preference one or the other? And if so, maybe you can talk about the rationale as to why?

Yes. So in response to the first question, I would say we are moving both forward. We have thought in our minds that we would bring one into the clinic by the end of this year. It's not final yet, but that is certainly our current inclination. Both are equally compelling. It's hard to choose between them, to be very candid. I think our preference because of the potential in these diseases is to bring them both forward as quickly as possible, but we're trying to work a balance between resource deployment and the opportunity that they represent.

Okay. And then I know you mentioned that there's about 150 neutrophil mediated diseases that you are looking at and from the screening, these indications kind of were given preference. So I just wanted to know like potentially, would Brensocatib find applications in some percentage of that number that you had mentioned?

Yes. To be clear, we think that what we've unlocked here is the DPP1 inhibition pathway that, that interference with the inflammatory cascade is really quite profound in its potential application. So we start with these 4 indications, which rise to the top as the most probable for impact. But to remind you, we've already done preclinical work and other indications as well. like rheumatoid arthritis and lupus nephritis and some other very substantial indications. For a variety of reasons, it doesn't make sense for us to pursue those clinically, but we certainly are protecting them from an intellectual property standpoint. And so where that preclinical work gets done and validates its potential application, we have -- we pursued the IP around that. Would we go into diseases beyond this? If we had the resources down the road, yes, we would. I think this pathway presents a very substantial and broad opportunity. I can't emphasize that enough. And I think as we learn more and the scientific rationale is clear and the patient need is clear, those are things we will continue to evaluate and seriously consider pursuing.

We currently have no further questions. So I will hand over back to Will Lewis for any final remarks.

Thank you all for joining us this morning.

This concludes today's call. Thank you so much for joining. You may now disconnect your lines.