Good day Ladies and gentlemen, and welcome to Insmed Conference Call to discuss the Company's First Quarter's Financial Results. [Operator Instructions]. As a reminder, this conference call is being recorded. I will now like to introduce your host for today's conference, Blaine Davis, Head of Investor Relations. You may begin..

Thank you. Good morning, everyone and welcome to today's conference call to discuss our first quarter financial results for 2019. Before we start, let me remind you that today's call will include forward looking statement 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 from the results discussed in the forward looking statement.

Please refer to our filings with the SEC 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 Insmed Executive Management team including Will Lewis, Insmed Chairman and Chief Executive Officer, Paolo Tombesi, Chief Financial Officer, and Roger Adsett, our Chief Commercial Officer. Once we complete our prepared remarks we will open the call for your question.

With that, let me turn the call over to Will..

Thank you, Blaine. Good morning, everyone and thank you for joining us. We are very excited about the progress of the U.S. launch of ARIKAYCE. Two full quarters into launch we continue to see encouraging trends and have received positive feedback from both patients with refractory MAC lung disease and treating physicians.

While much more work remains we continue to gain confidence in the near term and more importantly the long term potential for ARIKAYCE. We continue to see steady growth of new patients initiating therapy, as well as an expansion of the breath of prescribers.

We believe we are starting to see a more consistent rate of discontinuations and we continue to see strong support from the payer community. Overall, we are off to a great start on the U.S. launch and are optimistic for the potential for ARIKAYCE to help patients with refractory MAC lung disease.

Roger will spend more time on some of the launch specifics in just a few minutes. As a result of our strong early performance over the first two quarters of launch, we are raising our full year revenue guidance to 90 million to 105 million from our previous guidance of 80 million to 90 million.

Now let me provide an update on our strategic priorities for 2019. Our first and most important priority remains Our execution of the U.S. launch of ARIKAYCE.

We continue to refine our understanding of the market as we move out of the early launch phase we plan to continue to ship resources and focus our execution in areas that we believe will allow for sustained long term growth for the ARIKAYCE franchise. Beyond the U.S.

launch of ARIKAYCE and it's current indication, we have been working diligently on the post-marketing confirmatory study, which is required for the full us approval of ARIKAYCE and will be conducted in a frontline setting of patients with MAC lung disease.

We also expect to initiate a study later this year in and NTM lung disease caused by Mycobacterium abscessus. Mycobacterium abscessus is a particularly virulent pathogen and the second most common cause of NTM lung disease.

You may recall the interim data from an investigator initiated study supported by Insmed of ARIKAYCE in Mycobacterium abscessus patients were presented last year at the American Thoracic Society meeting and showed roughly 30% culture conversion by month six with ARIKAYCE, a promising result in these patients.

Updated data from that trial will be presented at ATS 2019 later this month. We expect to meet with the FDA in the coming weeks to further discuss both the post-marketing study and a frontline setting and the Mycobacterium abscessus study.

Importantly, the FDA just recently brought together leaders from industry and the NTM treating community to discuss a number of aspects of the clinical study of NTM.

Insmed was an active participant in that discussion and we felt the meeting was very productive and moving closer to a defined set of clinical endpoints that could be used for frontline study of ARIKAYCE.

If our clinical studies are positive, and we see approval from regulatory authorities we would see a dramatic expansion of the addressable patient population for ARIKAYCE representing a substantial opportunity to serve patients with unmet medical needs for years to come.

By completing our post marketing study and advancing our lifecycle management programs, pardon me, beyond completing our post marketing study and advancing our lifecycle management programs. We are very focused on our global expansion plan to support potential regulatory filings for ARIKAYCE outside the U.S.

In Europe we remain on track to file by the middle of this year, we continue to anticipate filing in Japan in the first half of 2020. These regions represent an important opportunity to serve patients suffering from MAC lung disease worldwide and with appropriate regulatory approvals to add to our top line growth.

To that end, I am pleased to share that we have appointed Neil Hughes as Head of Europe, Middle East and Africa, effective June 1 to drive forward our launch preparations in Europe. Neil joins us from Shire where he most recently served as General Manager of Endocrinology. We look forward to welcoming Neil.

Beyond ARIKAYCE, we continue to make steady progress with the Willow Study, our six month global Phase 2 trial of INS-1007 in patients with non-cystic fibrosis bronchiectasis. At this stage, I'm pleased to announce we have reached our target enrollment of 240 patients. We continue to expect Phase 2 data to be available in early 2020.

This program is a very exciting part of our pipeline that, like ARIKAYCE has the potential to address a significant unmet need. INS-1007 utilizes a novel mechanism of action to potentially treat patients with non-cystic fibrosis bronchiectasis, who currently have no therapy approved for this specific indication.

If the results are positive, we would expect to advance INS-1007 into registrational trials for non-CF bronchiectasis. In parallel, we are advancing INS-1007 into Phase 2 trials for the potential treatment of Granulomatosis with polyangiitis or GPA.

We're also advancing our INS-1009 program for the development of an inhaled formulation of treprostinil and we will have some interesting preclinical data to present at ATS 2019. We have had a very strong star to 2019 and are excited for what the rest of the year holds for us.

Let me now turn the call over to Roger who can provide some additional insights into our commercial activities.

Roger?.

Thanks, Will. Good morning, everyone. As Will mentioned earlier, we're very excited about the U.S. launch of ARIKAYCE thus far. Let me take a moment to walk you through some of the details of our performance today.

First, I'd like to discuss an update on our addressable patient population leading up to and at the time of our launch, we estimated our addressable patient population to be about 10,000 to 15,000 patients, those with MAC lung disease in the U.S.

who had limited or no treatment options, in-line with the language in our FDA approved label, and the patients we studied in our pivotal Phase 3 trial. We now believe that the addressable population is between 12,000 and 17,000 patients. We have made this adjustment based on the growing overall MAC lung disease population.

This means we may now have the opportunity to reach even more patients who are currently suffering in the absence of a treatment paradigm that works for them. We are very pleased that in the first quarter of 2019, which was the second quarter of our launch, we reported net sales at $21.9 million of which $21 million is attributable to the U.S.

launch and $900,000 is attributable to our compassionate use programs in France and Germany. Now let me take a moment to walk you through some of the metrics we're using to measure launch performance in the U.S. beyond revenue.

As a reminder, for the fourth quarter of 2018, we reported that more than 500 patients had initiated treatment with ARIKAYCE and approximately 600 physicians had written at least one prescription. In the first quarter of 2019 we are seeing strong new patient demand with over 650 new patients starts in the quarter.

We also continue to see strong prescribing trends with approximately a1000 unique ARIKAYCE prescribers since launch. We believe these metrics reflect the fact that the patients are clearly there and the physicians have an intent to treat. While we are still early in our launch, we continue to review these results as very encouraging.

Let me now spend some time on additional metrics that we believe are helpful in understanding how the product is being used and reimbursed to-date. As Will mentioned earlier, we believe we are seeing a stabilizing rate of discontinuation, with a patient dropout rate that is slightly better than the 34% we saw in the clinical study.

We are closely monitoring this metric and believe that 2 important factors that influence continuation of therapy are physicians gaining more experience with ARIKAYCE and our robust Arikares support program which is intended to help patients through their treatment journey.

We believe this support will help set appropriate expectations of possible side effects for patients initiating therapy. In addition to monitoring patient discontinuation rates, we are also carefully monitoring adherence to the treatment regimen.

While the data is early and somewhat limited, we are seeing adherence in line with our expectations and within the benchmark rates of adherence of between 60% and 70% seen with other inhaled antibiotics.

Keep in mind it's consistent with our label for patients to take a short break from therapy to manage side effects and then resume therapy as medically appropriate. This will necessarily reduce the adherence rate, but potentially allow patients to persist with ARIKAYCE. Turning to reimbursement, we continue to see strong support from the U.S.

payor community. Through March, plans covering over 150 million patient lives now provide access to ARIKAYCE and plans covering over 70% of commercial lives have an ARIKAYCE coverage policy in place.

Medical acceptance continues to be the dominant path to reimbursement in the Medicare population and we are currently seeing approximately 80% approval rates through that process. To date, for approximately 55% of patients, reimbursement comes from Medicare, while for approximately 36% of patients, reimbursement comes from commercial plans.

For the remaining patients, reimbursement comes from Medicaid, TRICARE or other means, including cash pay. We remain encouraged by the positive reimbursement trends and the fact that ARIKAYCE is generally being reimbursed through physician attestation for appropriate refractory MAC lung disease patients.

We are working to ensure that that process continues. As I have said before, I believe we have the right strategy, an exceptional team, and the necessary resources to maintain that launch momentum throughout 2019. Turning to our global expansion, we continue to advance our regulatory strategy in both Europe and Japan.

In Europe we remain on track to file by the middle of this year and we continue to anticipate filing in Japan in the first half of 2020. We are extremely encouraged by the potential of ARIKAYCE in these regions and are investing in the infrastructure to be fully prepared for potential commercial launches.

We are all very excited about the launch of ARIKAYCE at this early stage, and look forward to sharing our progress with you throughout the year. And with that, I'll hand the call over to Paolo..

Thanks, Roger. Good morning, everyone. I will spend just a few minutes reviewing our first quarter financial results and then we'll cover our financial guidance. This morning, we reported total revenue of $21.9 million, comprising $21 million of U.S. net sales of ARIKAYCE and $900,000 of ex-U.S. net sales of ARIKAYCE. The ex-U.S.

net sales reflect utilization from the Compassionate Use programs in both France and Germany. As you will see on our income statement, for the first quarter of 2019, we reported a net loss of $74.2 million or $0.96 per share compared with a net loss of $68.5 million or $0.89 per share for the first quarter of 2018.

Our gross to net for the quarter were approximately 14% as expected. This is a slight increase from the fourth quarter and was largely attributable to the coverage gap as a result of the donut hole reset at the beginning of the calendar year. Cost of goods sold for the first quarter was $4.2 million.

As expected, the gross margin improved during the quarter to 81%. It is important to remind everyone that our gross margin will continue to benefit in 2019 from expanded inventory produced prior to the FDA approval of ARIKAYCE. Research and development expenses were $31.2 million for the quarter compared to $30.1 million in the first quarter of 2018.

SG&A expenses were $54.8 million for the first quarter of 2019 versus $32.7 million in the first quarter of 2018.

The increase was primarily due reinsurance an increase in headcount including the hiring of our salesforce, and higher expenses related to commercial activities for ARIKAYCE, including data awareness, patient support activity and field operations. We closed the first quarter of 2019 with $420 million in cash and cash equivalents.

Let me spend now a moment reviewing our financial guidance for the first half of 2019. The company is investing in the following key activities in 2019. First, the continued support of the U.S.

launch and commercialization of ARIKAYCE; second, our post-marketing confirmatory study of ARIKAYCE, which will be conducted in a front-line setting as required for the full approval by the FDA as well as clinical trials to support the life-cycle management of ARIKAYCE, and the WILLOW Study, our Phase 2 development program for INS1007, along with advancements of other pipeline programs; third, our global expansion in Europe and Japan to support regulatory and pre-commercial activities in these regions; and fourth, the build-out of an additional third-party manufacturing facility for increased long-term production capacity of ARIKAYCE and a new corporate headquarters facility.

As a result of these activities, Insmed continues to expect cash-based operating expenses to be in the range of $150 million to $170 million for the first half of 2019.

As a reminder, we define cash-based operating expenses in our earnings press release as total cost and expenses excluding cost of product revenue, stock-based compensation expense, depreciation and amortization of intangibles.

In addition, the company expects capital expenditures in support for the large-scale manufacturing facility at Patheon and the new headquarters to be in the range of $25 million to $35 million for the first half of 2019. The majority of our cash expenditure remains stage-gated and are predicated on continued success of the U.S. launch.

In this way, our expenditures should be seen as an investment to support potentially significantly expanded revenue growth, both here and around the world. As already mentioned by Will, in terms of revenue guidance, we now expect full year 2019 revenue for ARIKAYCE to be in the range of $90 million to $105 million.

With that, I will turn it back to Will..

Thanks, Paolo. Let me close out our prepared remarks by reiterating that 2019 has been a very exciting year for us so far and we have made tremendous progress in helping patients suffering from refractory MAC lung disease. We are executing well against our strategic priorities while also generating significant value for shareholders.

We are well on our way to achieving our vision of building a leading bio pharmaceutical company that empowers great people to deliver, with a profound sense of urgency and compassion, life altering therapies to small patient populations experiencing big health problems.

With the potential global expansion of our ARIKAYCE franchise, our continuing efforts to successfully execute our lifecycle management plans, and the potentially significant value of our pipeline, we believe we have an exciting future ahead. As always, I'd like to thank the Insmed team for their hard work and dedication.

We have an exceptional team whose talents are clearly demonstrated by our recent success. And finally, I want to thank the patients and physicians we serve for their continued involvement in our clinical program and their valuable input into how we can serve them better. We are here to make a difference in the lives of patients and their families.

And every day, we work hard to achieve this very important goal. With that, I'd like to open the call to questions.

Operator, can we take the first question, please?.

[Operator Instructions]. The first question comes from Martin Auster with Credit Suisse. Please go ahead..

Hey, guys, congrats on the quarter. Thanks for taking the question. I have a couple on I guess on the reimbursement side. I think very encouraging clinical and reimbursement updates so far. Curious, as you start seeing ARIKAYCE getting adopted in the formulary if you're seeing changes, any meaningful changes in kind of net price that you're realizing.

And if you have a sense of kind of what the average out of pocket costs for patients looks like.

And then over on kind of the international business, I was curious if you'd found any data or have any sense of kind of how that ATU price you're currently realizing in France and Germany, how that might translate to kind of an improved commercial price if there is any kind of data or any comparable situations you've uncovered. Thanks..

So Roger, do you want to take the reimbursement question of ex-U.S.

price as a predictor?.

Yes, happy to take this question. Thank you. Yeah, so as you mentioned, we're also very pleased with the payor progress we've made to date and we continue to see that primarily physicians are being asked for attestation for the appropriate patients.

We did see, as Paolo had mentioned in the first quarter, an impact on the gross to net, basically associated with the Medicare donut whole reset. So that impacted our GTS slightly in the first quarter.

We had mentioned previously that we would strategically contract as necessary to secure access and make sure that the patients and physicians have smooth access and the appropriate prioritization. To date we have not yet entered into any contracting arrangements. We've been very pleased with the reception and the processing of the PAs for the plans.

So we haven't had an impact on a price specifically tied to any contracts to date. As far as Europe and the ATU price, there is no update to give on that.

I would say generally the ATU price is primarily viewed more as a ceiling than a floor, but certainly our ambition will be to secure an EU net price that would be closer to that ATU price than below it..

I think we're still getting just north of 80,000 Euros in the ATU setting..

That's correct. Thank you..

The next question is from Adam Walsh with Stifel. Please go ahead..

Good morning. Thanks for taking my questions. I've got 3 quick ones here. The first one for Roger. Roger, in terms of the payor, what are you seeing on the payor side with respect to 6-month reauthorizations, some of which should now have turned over.

Are you seeing any commonalities or themes there that we can read from? For Paolo, can you speak to kind of the cash-based OpEx guidance for the second half? I know you reiterated today the first half guidance.

What are you thinking about for the outlay in the second half? And then thirdly for Will, on INS1007, can you just talk about GPA really quickly, the mechanism of action of 1007 and how it might fit what that? And also, the timing of the trial launch and anything you can say about the design. Thank you..

Hi, Adam, thanks for the question. It's Roger. I'll just talk to you about the question around the reauthorization. From a payor perspective, you're right, we're starting to see some, that time period where we will start to see some reauthorizations coming through.

I will say that different plans are putting different timepoints around when those authorizations will occur. And physicians are writing prescriptions for different lengths of therapy. But generally, I would say that our education efforts around giving time, giving at least 6 months and then time for their sputum tests, are paying off for us.

And more broadly, the general theme from payors as to a reauthorization is that the attestation from a physician that either the clinical benefit is apparent for the patient and therefore it's appropriate to continue therapy for this patient, or in fact that the sputum has converted and therefore according to guidelines, there will be another 12 months of therapy indicated for that patient.

So I would say that we're really pleased so far with how payors are thinking about the reauthorization process for these patients.

This is Paolo on the guidance. As you mentioned, Adam, we have this morning reiterated the guidance for the first half to $150 million to $170 million. We confirmed the key strategic priorities for the company being the U.S. launch, global expansion pipeline and the manufacturing field tests. We are not giving guidance for the second half.

What we mentioned that in any case we see very rigorous stage-gated approach that is predicated to the success of the U.S. launch..

I think, look, we're just in the growth phase right now, so we're deploying capital proportion to the success we see on the revenue line. And that's why you see the spend where it is. If that were to change in some way, we obviously would revisit the rigor or the aggressiveness with which we're deploying capital.

Your question on GPA, I'll just take a moment to touch on this. Both on GPA and then the mechanism of action. GPA is a type of GPA is a type of, that's granulomatosis with polyangiitis. GPA is a type of vasculitis which is a kind of inflammation of blood vessels. So in GPA, the cells involve the inflammation of neutrophils.

So 1007 has two sort of mechanisms of action. One is fairly specific to GPA in that it decreases the expression of proteinase three in the neutrophils. So as a result, it's expected to be less activation of the neutrophils by the anti-neutrophilic cytoplasmic antibodies or ANCAs.

And so that is the aspect that is the most intriguing to experts and makes them think 1007 could be better than other less specific anti-inflammatory agents. The second potential mechanism of action is the same thing that makes it interesting in other neutrophil driven inflammation like non-CF bronchiectasis.

In that 1007 decreases the production of active neutrophils serum proteases, all 3 of them including proteinase 3, neutrophil elastase and copeptin [ph] G which contribute to the damage that neutrophils can cause when they are recruited to tissue in excess of endogenous levels.

So in this way, it's potentially impactful in ending neutrophil driven inflammation and one of the reasons we're so excited by it. I know there are other companies that have DPP1 inhibitors out there. Ours is the most advanced, I'll just remind you of that, and it is also reversible.

So we are super excited that we've got 240 patients recruited and that topline results should be out beginning of next year. For GPA, I'll just add that those trials in Phase 2 are going to kick off this year..

The next question is from Ritu Baral with Cowen. Please go ahead..

Good morning, guys, thanks for taking the question. A couple for me.

The first one is, the attestation as the main step edit, can you guys talk to any other prior authorization requirements in any of the plans even if attestation is the most frequent? What else should we be thinking about as far as prior auth?.

Hi, Ritu, yes. So thank you. So primarily it is attestation. And as we talked about, the education efforts we've been making with payors has been I think particularly fruitful. So they are very much focused on the appropriate patient.

So what they want to hear from the physician is that this is a refractory patient, so they've been exposed to at least 6 months of therapy of combination antibiotic therapy prior to being considered for ARIKAYCE, and that they're got a definitive diagnosis of NTM MAC disease.

And that typically includes a culture or a CT scan to make sure that these patients are the appropriate patients. So I would say that that's where they're primarily focused on is that it's very consistent with the label..

So it's basically attestation of retrospective 6 month treatment with other treatments.

Nobody is requiring a prospective 6 months with the guidance-based therapy currently?.

To my knowledge, they are happy with a lookback. There may be some plans that have put a time limit on that and I'm trying to remember, but I believe I've seen a plan that said within the last 12 months there has to have been at least 6 months of therapy.

But I have not to my knowledge seen a proactive you've got to now reinitiate for another six months before you're eligible for ARIKAYCE..

Got it, that's helpful. Then you mentioned expansion of the prescriber base. Can you characterize the new prescribers that have come onboard in Q1? How is the ID versus pulmonology mix, Centers of Excellence versus community setting, that sort of thing? Then I have one last follow-up..

Sure. So I think it's been remarkably consistent actually with our fourth quarter experience. Slightly more pulmonologists than infectious disease specialists, but only slightly more. So predominantly the prescribing is coming from those 2 specialists, pulmonologists and infectious disease specialists.

Most of the prescribing is coming out of our Tier 1 physicians. That reflects not just the broad community pulmonologists and IDs, but also the centers of excellence. Those are, as you would imagine, on a per physician basis, those are the most productive physicians because they have the most patients.

But we are seeing broad-based prescribing beyond the centers of excellence with the pulmonologists and the IDs..

And I just want to add my enthusiasm for what that means for the company. Because if you look at any of the studies that indicate what yields success in the medium to long term of a launch, it's the ability to engage with and have community level physicians writing those 1 to 5 prescriptions over time.

And to get this many physicians, this broad, this early, is really a very strong sign, so super excited about that fact..

Is it fair to say that all of the 1,000 prescribers have had calls from the salesforce or even repeated calls from the salesforce? Are they sort of tracking in line? And how much further -- I guess what's the penetration, the call rate penetration in your targets and how many do you have left?.

So I would say that actually not all of the prescribers have received a call from our therapeutic specialists. So as we talked about previously, right, so we've got our 2 tiers covering about 5,000 physicians. So 2,000 in Tier 1, 3,000 in Tier 2.

Then there's a remaining sort of over 11,500 healthcare professionals and they account for about 30% of the potential NTM patients.

So we're not sized to cover all of those physicians and so there is some interest as you can imagine for the first approved therapy for this disease, and some of the physicians will certainly prescribe without seeing a therapeutic specialist.

One of the things that we've been investing in beyond just the therapeutic specialist reach is speaker programs. And so we have experts who we think are very important in carrying the message of how to treat these patients with ARIKAYCE.

We have a pretty comprehensive speaker program network where the experts can educate peers on how to use ARIKAYCE and to think about how to manage this NTM MAC disease. And that's something that we think is particularly important and effective. We haven't updated the metrics on the reach.

We continue to reach a very high percentage of our physicians and we expect that to grow over time. But as I said, the impact on prescribing ARIKAYCE is beyond just the therapeutic specialists making a call, a single call to the physician. It's the efforts that we put all around that, including our digital and our education campaigns..

And I just want to add to that my enthusiasm because we focus a lot of the therapeutic specialists and their efforts, and there is no question that they have done an excellent job here. But it is masked by the excellence of our marketing group here at the company, and both in digital another forms.

I think one of the things that's going to be happening later this year which we think will be additional wind in our sales is that we're going to have a branded campaign launch. Because we're now past the point where we can release that. So we're super excited about that campaign.

It's tested very well and hopefully we'll see that reflected in our numbers in the future..

Got it.

Last question, you guys are on the market and everything, but why this time period before finalization of the confirmatory trial design? Are you guys still having breakthrough designation-like conversations very real time? Is the FDA waiting for these roundtables and panels? I guess what's the delay?.

This is consistent with the timeline that we had agreed to with FDA, so we are right on track.

I think the only thing that is new that is interesting and I mentioned it in my comments briefly, but I'll just touch on it a little bit further here, was that the FDA asked for a panel, sort of convened a panel, to look at what endpoints and trial design elements should be considered when doing NTM trials specifically.

So this was a daylong panel where they brought in experts, they brought in physicians from across the country, they brought in patients to ask them what's important to them. They invited us to participate on the panel directly and we had Dr. Gene Sullivan in that role.

And then we were also asked to present to the panel which we did directly through other members of our team.

I think that entire day was extremely positive and that it raised a number of different potential avenues that could contribute to things like shortening the trial length, how we look at comparator elements within the trial, and what we measure for primary endpoints.

So I think overall we come away from that which happened just a couple of weeks ago with a very strong and positive feeling about where we're going to end up. And as I mentioned in the comments, we're going to be talking to the FDA in the aftermath of that about our final trial design here in the coming weeks.

So right on track, feel very good about where are, and should have information in the not too distant future based on where those discussions go..

The next question is from Dewey Steadman with Canaccord. Please go ahead..

Hi, guys, thanks for taking the question.

I guess how should, with the WILLOW study and bronchiectasis, is there a COPD component of patients in the trial or have they been excluded entirely?.

You know what, I'm going to have to get back to you on that. I can't recall out of the gate whether we have COPD included in it or not. I apologize that that. But I know that what I would say about this and where we're particularly focused is that non-CF bronchiectasis overlaps about 40% with NTM. So about 40% of non-CF bronch patients have NTM.

So when you think about the logic and strategic value of this trial and what it could mean for us, not only does it represent a significant expansion of potential patients we could treat, but it's directly in the wheelhouse of our therapeutic specialists in terms of their call point..

Great.

I guess what were the specific factors that led to your patient population expansion or patient population estimate expansion? Was it just more knowledge that you're getting as you're detailing docs? Or is it broader awareness of NTM in the ID community?.

I'll ask Roger to comment on it from his perspective and then I'll just remind you that the NIH estimates that NTM is growing about 8% to 10% a year and we know from claims databases that there are about 100,000 diagnosed NTM Patients in the U.S.

But beyond that, I know that we've done some excellent work using machine learning that maybe Roger, you can comment on in terms of what it suggests..

Sure. So Dewey, I think the primary driver has been that prevalence growth, right, the 8% to 10% per year that we believe from the literature that we're seeing, the NTM population driving. And then there's some, I'm probably oversimplifying it a little bit, but there's some puts and takes on that.

But ultimately it comes down to that 12,000 to 17,000 refractory as we work through our funnel. We feel very confident that the population is expanding. I think that there is certainly an increasing awareness for NTM. I think certainly now that there's a therapy available, physicians are more willing to diagnose.

As Will mentioned, we had done some machine learning with the Symphony database and identified with a very high confidence level that there is approximately two NTM likely patients, so these are patients already in the system, working their way through the medical system to try to get an accurate diagnosis.

And that's something that we have some work to do there. I think it's incumbent on us to help educate physicians and help educate patients about the possibility of them having that NTM disease and getting that accurate diagnosis. And to that end, later this year we'll be kicking off a patient branded campaign as well to raise that awareness.

As we look at the Symphony database and as we look at the definitive diagnosis through the ICD codes, we see that there is an increase consistent with what we expected from the literature. So we feel very good about that increasing prevalence number..

And just to be clear, when he said there are two patients, he means two patients for every 1 diagnosed currently. So that would be an additional potential 200,000 undiagnosed patients that we believe are going to make their way through the system.

So that portends really interesting things for us in the future as disease awareness continues to take hold and the appropriate patients who become refractory for frontline treatment find their way into the physician to potentially get the benefit of our drug..

Thanks. My last question, I guess it's out of your control, but could you give, maybe opine a bit on the ATS IDFA guidance and the potential for that to be updated.

Is that a near-term event that we should be thing for?.

You bet. So let me just comment generally on why we think 2019 from here gets to be pretty exciting. We have a number of positive things that we anticipate we'll rollout later this year one of which is ATS.

That's in May and we'll have some data and we'll have a pretty big splash there, so hope to see a lot of you at the American Thoracic Society in Texas. The second, as you mentioned, is the guidelines. We anticipate that the guidelines will be updated for the first time in close to a decade.

And since we are the only approved therapy out there, we are hopeful that we will be included in them. And that certainly hasn't impeded our ability to have success to date, but we think it could be an additional point of support as we go forward. The third is, we both mentioned, is the branded campaign which will be launching here shortly.

We're excited about what that can do to raise awareness and get patients to treatment. And finally, later this year we'll see additional conferences that will highlight the importance of the disease and potential value of our treatment, that's ID Week and CHEST.

So here through the end of the year, we've got a lot of positive catalysts that we think are going to potentially drive us forward. So we are super excited about it. One of which is the guideline update that you mentioned..

The next question is from Joseph Schwartz with SVB Leerink. Please go ahead..

Hi, guys, thanks very much. So I was wondering, to follow on to some comments that were shared earlier, how you are thinking about the most likely design for a confirmatory study may have evolved since all of your interactions with the FDA and treatment community recently.

Where does the consensus seem to be heading in terms of clinical endpoints? And then do you have any broad strokes thoughts on how you think the drug, and also control, would perform in the most likely addressable population and what the size of a confirmatory study needs to look like as a result?.

I appreciate that question and I wish I could give you a more specific answers at this stage. We've had, as I mentioned, very good discussion with the FDA.

I think our trial objectives, at least from our perspective, are aligning very closely with what FDA is looking for and I think that our design and their desire are matched and matched in a very positive way for the potential benefit of patients. So I am excited about where there trial designs are going.

They are not finalized yet and so I'm hesitant to offer any additional detail at this point until that's all locked down. As you know, these dialogues continue to evolve right until the last minute. But I think it's not too far in the future.

What I will say is that we are targeting now and will be discussing in the coming weeks, both the frontline trial design and the potential for a trial in M. abscessus. That is exciting because as you know from the ATS interim data last year, we saw a 30% culture conversion rate in M.

abscessus from an investigator-initiated study using our drug and that portends really good things and potential for our drug in that population where there is a clear need. And to put these in perspective, the M. abscessus population is probably close to equivalent in number of addressable patients to the refractory MAC population in the U.S.

And as we look at frontline, that is certainly severalfold larger than our current addressable population. So these represent really significant expansions if and when we're able to come to agreement with regulatory authorities if there's a path to approval and I would just say at this moment we're very hopeful about that..

Great.

Then regarding the NTM treatment guideline update, to what extent is the community already practicing in line with what you expect the new guidance to say? And to what extent do you think it will lead to different usage patterns? Can you help us appreciate how this new guidance will impact adoption of ARIKAYCE in your view?.

As I said before, it hasn't -- our lack of inclusion in the guidelines has not impeded the uptake as we've seen it out there because we are the first ever approved therapy and people recognize that.

I think the approval of the guidelines, we obviously have no insight into what first of all, whether we're going to be included, and what they are even considering. My expectation would be of course that they would bring the guidelines in line, our drug in line with our label so that this would be for refractory patients.

And I wouldn't expect that that aspect would alter treatment paradigms at all. I think what the guidelines really bring in their reissuance is more of that energy around NTM disease state awareness and the appropriate way to treat these patients.

We are picking up significant momentum through our disease awareness campaigns that have been going on for a long time. That's going to continue. You've heard Roger talk about the speaker panels that have been out there talking about this.

I think all of that is positive in terms of how it raises awareness and potentially helps patients get an effective therapy. Being that the current standard of care, or if they fail that, the potential use of our drug. So I think we're about in as strong a position as we could possibly be as well look toward the rest of 2019..

Great.

Then if I could just sneak one in on the WILLOW study, I know that data is a little ways away, but what would you like to see there? And how would it, how would you expect that it will inform the design that you're contemplating at this point beyond the current trial?.

So just to frame out the WILLOW study for everybody, this is the study that is 3 arms, it's placebo versus 10 mg and 25 mg over a 6-month timeframe followed by a one-month follow-up for safety and evaluation. At the conclusion of which we'll have topline results. The primary endpoint is time to pulmonary exacerbations.

We're looking at 4 secondary endpoints. One is the rate of exacerbations, second is a measure of how patients feel, the QLOV instrument. We're looking at FEV-1 and then finally we're going to track neutrophil elastase levels in sputum. So the collection of all of that data I think will be able to inform a careful design of Phase 3 studies.

We anticipate there would be two of them. The key here is that the primary endpoint, time to pulmonary exacerbations, is the primary endpoint that the FDA has agreed upon to be the appropriate one for full approval of the drug. So we're measuring the right thing.

If we're able to see a clear impact here, and with 240 patients, we anticipate we should be able to, this trial should inform very specifically how to go forward in a Phase 3 trial.

And if not, I just want to highlight, as I discussed in the mechanism of action earlier, 1007 is a DPP1 inhibitor has the potential to impact a couple of inflammatory diseases. We are looking at non-CF bronch in Phase 2 as our first and most promising, but right alongside that is GPA.

And we think that that is a very high probability of success and are excited that those Phase 2 trials are going to be up and running as well. So more to come on this program in the future, but the first data will hit in the beginning part of next year and will absolutely inform whether we go forward into Phase 3..

We don't have any additional questions. I would like to turn the conference back over to Will Lewis for any closing remarks..

I just want to close by saying how excited we are about the progress we've made to date in 2019. And for all the reasons I mentioned a moment ago, we've got a whole number of positive trends that are going to be supportive of us I think as we move forward. So thank you all for joining and we look forward to talking to you on the next quarter..

Conference call has now concluded. Thank you for attending today's presentation. You may now disconnect..