Good day, and welcome to the Insmed Fourth Quarter and Full Year 2019 Results Conference Call. All participants will be in a listen-only mode. [Operator instructions] Please note this event is being recorded. I would now like to turn the conference over to Eleanor Barisser, Investor Relations. Please go ahead.

Thank you, Elisa. Good morning, and welcome to today's conference call to discuss our fourth quarter and full year financial results for 2019 and provide a business update. Please note this conference call features slides which can be found on the Events and Presentations page of the Insmed website.

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 from the results discussed in the forward-looking statements.

Please refer to our filings with the SEC, which are available through the SEC's website at www.sec.gov or from our website, for information concerning the risk factors that could affect the Company. We plan to reference the non-GAAP financial measures during today’s call.

For a reconciliation of that measure to our GAAP results, please refer to the earnings release we issued earlier today. Additionally, 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, Chairman and Chief Executive Officer; Roger Adsett, Chief Operating Officer; Dr. Martina Flammer, Chief Medical Officer, Dr. Eugene Sullivan, Chief Product Strategy 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. Good morning, everyone, and thank you for joining us. 2019 proved to be a remarkable year for Insmed. We executed across all areas of our business and advanced our mission of transforming the lives of patients with serious and rare diseases.

The start of 2020 finds us with significant momentum having just concluded our first full year as a commercial enterprise, following the successful U.S. launch of ARIKAYCE and having released the top-line results of our Phase 2 WILLOW study in non-CF bronchiectasis.

In addition, several new members of the senior management team recently joined our ranks to help us accomplish our mission. These include, Dr. Martina Flammer, our Chief Medical Officer, Sara Bonstein, our Chief Financial Officer, and Fred Zussa, our Senior Vice President of Business Development.

Their arrival heralds the start of a new chapter in Insmed’s history as we prudently resource the advancement of several incredibly promising programs and international expansion efforts. Today’s call will also feature a more detailed look at our pipeline and the introduction of two new programs.

As you can see on Slide 5, with the talent resources and history of successful execution, Insmed is poised for significant potential growth over the coming years.

Importantly, what this means for our investors is that we are now a company guiding both commercial and clinical development in several programs, each of which we believe have the potential to generate in excess of $1 billion in revenue in markets with no alternative approved treatment options.

In particular, ARIKAYCE enjoys multiple layers of market exclusivity and has issued patent protection into 2035 in the United States, Europe and Japan and through 2033 in China. Similarly, for INS1007, we have broad patent protection into 2035 in the United States, Europe, Japan and China with the opportunity for additional patent extensions.

It is rare to find a company with a such of wealth of promising development opportunities for diseases with unmet needs built upon a successful commercial track record. Behind each of those substantial potential opportunities are a vast number of patients who will potentially benefit from first-ever approved compounds in their respective diseases.

This is what drives us to execute against these significant opportunities. 2019 was arguably the strongest year yet in Insmed’s history and our achievements across all areas of the business have laid the groundwork for our next wave of growth as we seek to build a leading global multi-product biopharmaceutical company.

Let me now turn the call over to Roger for an operational update.

Roger?.

Thanks, Will, and good morning, everyone. From an operational perspective, I am pleased to report that we are well positioned to execute on our strategy.

We continue to deliver across all areas of our organization including research and development, manufacturing, international expansion and commercial execution and look forward to another standout year. During today’s call, I want to primarily focus on our commercial organization.

As shown on Slide 7, I am pleased to report that we had a strong finish to the year maintaining the solid performance around the U.S. commercialization of ARIKAYCE and with continued inroads into our global expansion opportunities. Let’s now turn to Slide 8.

As we announced earlier today, we reported total net sales of $136.5 million for 2019, coming into the higher end of our guidance of $133 million to $138 million for the year. $132.1 million of these sales is attributable to the U.S. and $4.4 million is attributable to our compassionate use and named patient programs in France and Germany.

For the fourth quarter, we reported net sales of $45.7 million, with $44.3 million attributable to U.S. sales and $1.4 million attributable to our compassionate use and named patient programs. Sara will discuss our 2020 financial guidance later in the call, but I wanted to provide our perspective on the landscape in the year ahead.

We believe there are a number of potential catalysts at place we look to build upon our 2019 success. First, we expect a peer reviewed paper will soon be published that will provide potential practical solutions to address the most common adverse events that can accompany uses of ARIKAYCE in the treatment of refractory MAC lung disease.

Second, we anticipate the near-term introduction of new guidelines from multiple scientific societies including the American Thoracic Society or ATS and the Infectious Disease Society of America or IDSA, which we remain optimistic will support the use of ARIKAYCE for appropriate patients.

Third, while we made strong inroads with patients in the first 15 months since U.S. launch, there remains a significant number of the estimated 12,000 to 17,000 refractory MAC cases in the U.S.

still eligible for treatment and while we have made great progress in reaching physicians and have had over 1900 physicians prescribe ARIKAYCE, that leads approximately 3,000 of our initial targets who have not yet initiated patients on therapy.

Finally, 2020 will be the first year where we will begin to get a greater understanding of the duration of therapies for patients as well as the potential retreatment of patients who experienced a reinfection. With that said as background, I’ll first address new patient starts, which were approximately 550 in the fourth quarter.

This number is down slightly from the third quarter, but consistent with our expectations for variability of the metric quarter-to-quarter. In the fourth quarter, we anticipated a decline in patients initiating therapy around the year-end due to the holidays.

Early signs in the first quarter of 2020 indicated the annual donor effect resulting in an extended to fill prescriptions will be significant. As many of you know, at the beginning of the year, many patients’ deductibles reset forcing patients to pay out of pocket.

This could be particularly problematic patients insured through Medicare as Insmed is unable to directly assist patients with government insurance. As you may recall, approximately 55% of ARIKAYCE’s patients are insured by Medicare. This trend is common at this time a year when we do not expect its impact to extend beyond the first quarter.

Despite these two seasonal trends, we believe that for 2020 it is reasonable to expect new patient starts to remain on average, consistent with prior quarters.

We see a continued strong propensity to prescribe ARIKAYCE in the treating community and believe there are still many refractory MAC patients who have not yet been prescribed ARIKAYCE who may benefit from our products.

We expect to make steady progress with physicians to initiate appropriate patients on therapy and look forward to seeing how the growth drivers mentioned earlier play out over the course of the year. Growth remains steady in the number of prescribers with over 1900 physicians in the U.S. having written at least one prescription since launch.

We remained very focused on our efforts to increase the breadth and depth of prescribing. Recently, we have been engaged with those physicians with a history of prescribing ARIKAYCE.

With the expected upcoming publication of new treatment guidelines, and the peer reviewed publication proposing practical solutions to help manage adverse events, we intend to introduce a new initiative to target and educate those physicians with less experiencing treating refractory MAC.

We believe the impact of these new features in 2020 could serve to maintain commercial momentum. As we advance the U.S. commercialization of ARIKAYCE, we remain proudest with the patient experience.

We continue to invest in education of both healthcare professionals and patients to educate them on the potential adverse events associated with ARIKAYCE, as well as training on a nebulizer.

Discontinuations of ARIKAYCE in the first 90 days remains steady compared to the prior quarter and continue to trend better than the 34% reported in our Phase 3 CONVERT study. We believe this is the result of the appropriate setting of expectations with patients and physicians, as well as continued support from our Arikares patient support teams.

We expect that the publication of the paper proposing practical solutions to manage adverse events will further enhance these efforts. We anticipate that this discontinuation rate may improve slightly over time. We now have a large number of patients using ARIKAYCE in the U.S.

We are learning more about the average patient usage profile, but there are some important trends that remain to be seen. These include, direction of use for patients, as well as reinfection and subsequent retreatment rates which are not yet consistent enough to allow accurate forecasting.

We expect these trends will come into clearer focuses later this year. We expect the most significant potential catalyst impacting the patient usage profile will be the issuance of new guidelines.

We view their arrival as an important opportunity to reinforce the appropriate approach to treating refractory MAC patients including the recommended duration of therapy for these patients.

As a reminder, the current guidelines recommend treating with a triple combination that includes a macrolide, ethambutol, and rifampin to culture conversion, plus an additional 12 months on therapy. For patients who do not achieve conversion, these guidelines recommend that physicians evaluate whether there is a benefit to continuing therapy.

We are also closely monitoring adherence of the treatment regimen and we see a modest improvement over recent quarters with adherence remaining slightly above the benchmark rates of 60% to 70% seen with other inhaled antibiotics.

As far as reimbursement, we continue to experience a supportive payer environment and positive trends for ARIKAYCE with initial approval generally achieved through physician attestation for appropriate refractory MAC lung disease patients. We fully expect this practice to continue in 2020.

We also continue to observe that reauthorizations have not been an issue. We have executed a handful of contracts with major payers and continue to evaluate other potential contracting arrangements. We only plan to execute these when we feel that the terms are fair and will enhance access patients.

Turning to our global expansion efforts, as seen on Slide 9. In Japan, which as a reminder, has the highest diagnosed MAC patient population, we are on track to file for regulatory submission of ARIKAYCE in the first quarter of 2020, slightly ahead of our previous guidance of a first half submission.

In addition, we are extremely excited to announce a new strategic pre-commercial agreement in Japan. We have partnered with a top generic manufacturer and one of the approved components of the current MAC standard-of-care, a macrolide.

Unlike in the U.S., in Japan, the standard-of-care of macrolide, ethambutol, and rifampin is approved for the treatment of MAC lung disease.

Through this collaboration we are able to deploy an Insmed sales force that will be dedicated to educating Japanese physicians on MAC lung disease and promoting the appropriate standard-of-care regimen including use of a macrolide to treat patients.

We intend this innovative partnership to allow our sales force in compliance with Japanese law to establish and build relationships with physicians who are seeing and treating MAC lung disease patients. We expect to begin to hire our sales team in the first half of the year to execute on this opportunity.

In Europe, we continue to work with the European Medicines Agency or EMA with respect to our Marketing Authorization Application or MAA. The MAA has been validated by the EMA and we expect that if approved, we could potentially launch ARIKAYCE by the end of the year in Germany with the UK following shortly thereafter.

We continue to believe that the undiagnosed patient population is sizable in Europe. However, we anticipate uptake in Europe will be much slower than the U.S. because once approved, we will have to secure a pricing in each country before sales can be generated. The model in Europe in also different than in the U.S.

with a heavier focus on centers of excellence for the treatment of MAC lung disease. As such, we would not expect any material sales from a European launch this year, but rather we’d expect to see an uptake beginning in 2021. That said, we expect to continue to see compassionate use and named patient sales in 2020 with certain markets outside the U.S.

We have made significant progress with the commercialization of ARIKAYCE in the U.S. We are working diligently to maintain the strength of the brand and maximize the long-term potential of ARIKAYCE in the U.S., Europe and Japan.

I am very excited about what lies ahead and I want to congratulate the team for their continued commitment to the NTM community. In anticipation of additional launches and product demand from new geographies and label expansion opportunities, we are on track with our third and largest manufacturing facility.

We have partnered with Patheon and expect to bring this 450 liter facility online in 2021, which will more than double our manufacturing capacity. With that, I’ll hand the call over to our Chief Product Strategy Officer, Dr. Eugene Sullivan to provide an update around the clinical and development programs.

Gene?.

Thanks, Roger. This is a particularly exciting time for Insmed with a number of important clinical advancements taking place across all of our programs. I will address each of these. To begin with, we were thrilled with the outcome of the WILLOW study of once-daily INS1007 in patients with non-CF bronchiectasis.

Let’s now turn to Slide 11 for an overview. To remind you, INS1007 is a novel, oral, reversible inhibitor of dipeptidyl peptidase 1, or DPP1, an enzyme that catalyzes activation of neutrophil serine proteases, or NSPs.

NSPs are key mediators of neutrophil-driven inflammation, tissue damage, and excessive mucus production which are prominent features of bronchiectasis. The WILLOW data has highlighted a significant opportunity for Insmed representing a promising new approach to modulating neutrophil activity.

Given its novel mechanism of action, INS1007 could have applicability in a broad range of diseases resulting in a pipeline of products. We are proud to have what we believe to be the most advanced program in development leveraging this new mechanism of action and are pleased with this first data in non-CF bronchiectasis.

Bronchiectasis stands out as one of the more significant pulmonary diseases with no approved therapies. It is marked by frequent pulmonary exacerbations requiring antibiotic therapy and/or hospitalization. Prevalence estimates for non-CF bronchiectasis range from about 340,000 to 520,000 in the U.S.

with significant overlap with patients who have NTM lung disease. Given the strength of the top-line results we observed in the WILLOW study, we plan to focus the Phase 3 program on bronchiectasis patients with two or more exacerbations within the prior year.

According to our market research, this profile could represent approximately two-thirds of the potential U.S. patient population or 225,000 to 350,000 patients.

Slide 12, depicts the Phase 2 WILLOW study design, 256 adult patients were randomized to one of three arms, 10 mg of 1007, 25 mg 1007 or placebo for 24 weeks with a four-week post-treatment follow-up. Turning to Slide 13, which shows the baseline characteristics across the three groups. The patient demographics highlight the severity of the condition.

Over the 30% of patients have been hospitalized for exacerbation in the preceding two years, it is also notable to see that a significant portion of the patients had co-existing COPD or asthma, conditions where 1007 might also be expected to have an impact based on their underlying disease processes.

Turning now to Slide 14, based on top-line data, the WILLOW study met its primary endpoint of high to first pulmonary exacerbation over the 24 week treatment period for both the 10 mg and 25 mg dosage groups of INITIATIVES 1007 compared to placebo.

As we have previously disclosed, the pre-specified primary analysis demonstrated statistically significant results for both treatment groups with P values of 0.027 and 0.044 for the 10 mg and 25 mg groups respectively. Today, we can share the hazard ratios for each groups.

As you can see, for the 10 mg group, the hazard ratio was 0.58 with a P value of 0.029. For the 25 mg group, the hazard ratio was 0.62 with a P value of 0.046. We believe these results are compelling. For a patient, this means that the risk of having an exacerbation over the course of six months could be reduced by up to 40% when treated with INS1007.

Let’s drill down in this data and look at the hazard ratio by subgroups as shown on the four spots on Slide 15. Here you could see that for both the 10 mg and 25 mg doses, the point estimates of the hazard ratios favored INS1007 for nearly every subgroup. We view the consistency in this data across the various subgroups as quite compelling.

The only subgroup that falls to the right-side of the hazard ratio of one is the small group of patients aged 75 and older in the 25 mg dose group. There were only 14 patients in this subgroup, which resulted in very large confidence efforts. Let’s move on to Slide 16.

As we disclosed in our top-line release, treatment with INS1007 also results in a reduction in the frequency of pulmonary exacerbations versus placebo. This is an endpoint of particular interest, because the FDA has indicated that frequency of pulmonary exacerbation should be the primary endpoint in our Phase 3 program.

Over the course of the six month study, patients treated with INS1007 experienced a 36% reduction in the frequency of events in the 10 mg arm with a P value of 0.041 and a 25% reduction in the 25 mg arm with a P value of 0.167 versus placebo. We expect that our Phase 3 program will run for one year.

So we may see a magnified impact or more evidence of a dose response during that longer study. As we did for the primary endpoint, we also conducted a number of analyses to look at results for the frequency of exacerbations in various subgroups. The four slots for both doses are shown on Slide 17.

The results of these subgroup analyses were very similar to those seen with the primary endpoint with nearly all the point estimates favoring INS1007. Let me take a moment to address some questions we received about the dose response curve.

Because the effect sizes for the 10 mg and the 25 mg group were similar in the top-line analyses, it is reasonable to wonder whether the 10 milligrams is already at the top of the dose response curve for clinical efficacy.

We think it is very important to examine the data carefully in order to understand whether the 25 mg dose might be expected to offer important additional clinical benefit over the 10 mg dose particularly in the setting of a longer Phase 3 program. Therefore, we are conducting a series of additional analyses to further explore the WILLOW data.

For instance, we are evaluating weather factors such as randomization imbalances or outliers may have impacted the observed effect sizes and weather events that occurred soon after randomization before INS1007 could be expected to exert its effects may have obscured a signal of increased benefit of the 25 mg dose.

In addition, examination of secondary endpoints and pharmacokinetic exposure response modeling will help us to better assess both dosing options. I know some of you have asked if we have seen evidence of an inverted dose response, if that is not the case.

As we have drilled down into the data including the subgroup and sensitivity analyses discussed here today, we believe that we may have two viable doses to consider taking forward.

The top-line results suggest that 10 mg might be nearing the top of the dose response curve but additional analyses may suggest that 25 mg might provide additional clinical benefit in a longer Phase 3 program. We are very encouraged by the strength and consistency of the efficacy data across both does groups and patient populations.

Turning to safety shown on Slide 18. INS1007 was generally well-tolerated in the study. AEs were generally mild to moderate in nature. The most common AEs in patients in the WILLOW study were cough, headache, sputum increase, dyspnea, fatigue, and upper respiratory tract infection.

Interestingly, the incidents of adverse events leading to discontinuation of treatment was actually higher in the placebo group and in either of the active treatment groups with 10.6% in the placebo group, 7.4% in the 10 mg group and 6.7% in the 25 mg group.

When designing the study, we considered the generic abnormality that leads to near total absence of DPP1, a condition called Papillon-Lefevre syndrome. In this disease, patients experience symptoms that include periodontal disease and skin diseases.

We designed this study to look more thoroughly at these areas to see a far more modest inhibition of DPP1 would result in any such findings. For example, because of the concern around periodontal disease, we implemented a rigorous dental monitoring protocol for this Phase 2 trial.

Patients were examined by a dentist at baseline and twice during the course of treatment, which was intended to allow us to detect any evidence of potential effects. Treatment-emergent AEs were rated by severity and reassuringly, there did not appear to be any severe gingival periodontal events.

We will certainly share this data with the regulatory authorities, but do not anticipate a lead for similar comprehensive dental monitoring during the Phase 3 program. We will continue to analyze the data and look forward to presenting a more complete review of the results at the ATS Conference in May in Philadelphia.

We will also work with regulatory bodies to confirm the acceptability of our Phase 3 program. We are very pleased with the results we’ve seen in the WILLOW study. As a reminder, this is the largest Phase 2 trial ever conducted in bronchiectasis and the robust data from this trial reinforces our confidence in the program as we move into Phase 3.

Beyond bronchiectasis, we believe that INS1007 has the potential to be effective in treating other neutrophil-driven diseases including cystic fibrosis.

CF patients have even greater levels of serum neutrophil elastase than bronchiectasis patients and therefore we believe 1007 may also benefit CF patients by addressing the harmful effects of neutrophil elastase and inflammation and sputum production.

While our core development interest remains with bronchiectasis and CF, there is biological rationale to believe that INS1007 may be applicable across a broad range of indications.

For instance, DPP1 inhibition has the potential to be beneficial in areas such as asthma, in COPD, alpha 1 antitrypsin deficiency, GPA, inflammatory valve disease, lupus and rheumatoid arthritis. Our Phase 2 data may have unlocked a first-in-class mechanism with potential broad applicability.

We believe we are just at the beginning of the journey with INS1007 and look forward to optimizing its development in the years to come. Let me now turn to our efforts around label expansion for ARIKAYCE.

We are advancing ARIKAYCE in a frontline study, that if approved by FDA, would allow us to address the approximately 95,000 to 115,000 patients in the U.S. diagnosed with NTM lung disease and that will serve as a necessary to confirmatory study for ARIKAYCE as agreed in our post-approval requirement with the FDA.

We anticipate that this study will also address frontline approval requirements for Europe and Japan using the primary endpoint of durable culture conversion. We plan for a study duration of 13 months with treatment for 12 months followed by one month on therapy. The primary endpoint of this study in the U.S.

will be a composite patient reported outcome or a PRO in order to demonstrate clinical benefit as required by the FDA. As you can see in the latest study design captured on Slide 19, the validation of the PRO and the confirmatory study will run in parallel pending alignment with the FDA. We plan to initiate these trials in the second half of 2020.

ARIKAYCE holds potential in Mycobacterium abscessus, the second most common NTM pathogen. We plan to advance into a registrational Phase 3 study in this indication as well. Let me also provide a brief update around two additional pipeline programs.

As shown in Slide 20, behind 1007, we are advancing INS1009 for the treatment of Pulmonary Arterial Hypertension or PAH. We believe that 1009, our dry powder inhaled treprostinil prodrug formulation developed in our own labs has the potential to address limitations of existing prostinil therapies.

Not only does INS1009 have potential as a long-lasting vasodilator, it also has the potential to the disease modifies as it has been shown to significantly affect vascular remodeling in animal models of PAH.

In an animal model, INS1009 showed a better response than Sildenafil across a number of measures including Vasodilation, right ventricular hypertrophy, pulmonary arterial valve thickness and obliteration. We are planning for a steady cadence of data presentation around our work with INS1009 this year beginning with ATS in May.

Designed for once-daily dosing, INS1009 may prolong the duration of treatment effects and could offer PAH patients greater consistency in reducing pulmonary arterial pressure over time. INS1009 also has the potential to reduce side-effects associated with treatment. We intend to file an IND and initiate a Phase 1 study of 1009 this year.

Let’s now turn to Slide 21. Today, I am pleased to introduce a promising preclinical new chemical entity which we call RV94. We are evaluating RV94 for the treatment of gram-positive infections. This compound has been under development for several years in our labs.

RV94 is a Semisynthetic lipoglycopeptide designed to be used once-daily or less frequently by inhalation in CF patients with pulmonary MRSA infection.

By inhibiting peptidoglycan synthesis and disrupting the bacterial cell membrane, RV94 is designed to help reduce sputum bacterium load and by virtue of inhalation delivery to reduce systemic drug exposure.

From a clinical perspective, our aim with inhaled RV94 is to help improve pulmonary function and respiratory symptoms and to reduce the frequency in exacerbations and overall antibiotic usage. In an in vitro MRSA MIC assay, RV94 was 30 fold more potent than the existing standard of care antibiotic, vancomycin.

In addition, RV94 has shown up to 60 fold greater potency than Vancomycin for the treatment of gram-positive MRSA pulmonary infections in animal models. If further research continues to be supportive and if already RV94 were to be approved, this novel antibiotic would represent a major step forward in the treatment of CF patients with pulmonary MRSA.

Let’s now turn to Slide 22. Taking a step back, and looking at our product portfolio more broadly, we want to draw your attentions to the commercial overlap between our programs, particularly when you look at NTM, bronchiectasis and CF. In ARIKAYCE, we have an improved therapy for refractory MAC in the U.S.

We know that many CF patients also have NTM lung infection. According to the CF Foundation website, 13% of CF patients in the U.S. tested positive were NTM species in 2017. In addition, approximately 30% of bronchiectasis patients have NTM lung disease.

For 1007, with the positive WILLOW data, we are now one step closer to bringing forward a product for bronchiectasis and we have a new mechanism of action that we believe may help treat the inflammation and sputum production and CF. MRSA is becoming more common in CF patients and is now found in about 25% of patients with the disease.

Studies show having MRSA lung infections for longer than two years can affect survival rates in CF patients. Therefore we believe we have a unique opportunity to address an unmet need in CF with RV94. And with that, I’ll pass the call to our Chief Financial Officer Sara for the financial update. .

Thanks, Gene, and good morning, everyone. As you’ve heard from the team, 2019 proved to be a very productive year where we made significant progress across all of our programs while remaining keenly focused on the management of our operating expenses. As we saw in 2020, Insmed is well-positioned to support the next wave of its growth.

The cash flows from our ARIKAYCE sales are an important contributor in meeting our cash needs. As Gene just outlined, we believe we have several promising programs in development and we have the resources to take these programs to key value inflection points.

As a part of our longer term effort, we continue to explore business development initiatives and alternative financing options as potential sources of capital. Our quarterly and full year results are detailed in our press release issued this morning.

For today’s call, I want to draw your attention to a few key line items and share our outlook for the year. This morning, we reported total net revenue for the full year of 2019 of $136.5 million, comprising a $132.1 million in U.S. net sales of ARIKAYCE and $4.4 million in ex-U.S. sales of ARIKAYCE. The ex-U.S.

net sales reflect utilization of the compassionate use and named patient programs in both France and Germany. In terms of revenue guidance, as Roger mentioned, we anticipate 2020 will potentially see a number of significant factors play out making forecasting more challenging than usual.

Despite our challenges of accurately forecasting quarter-to-quarter last year, we delivered exceptional results exceeding expectations. Our takeaway is at the process of forecasting and this new indication is not straightforward and our current guidance reflects this uncertainty.

As the year develops and the various potential drivers play out, we will fine tune our preliminary estimates. With that said, for today’s call, we project revenues for the full year of 2020 to be in the range of $180 million to $220 million, as shown on Slide 24. We are extremely pleased with the commercialization of ARIKAYCE to-date in the U.S.

We will continue to focus on maintaining the strength of the brand, expanding our prescriber base, and reaching more appropriate refractory MAC patients who may benefit from ARIKAYCE. Our gross to net for the full year of 2019 were approximately 10%. We expect our gross to net to be in the mid-teens in 2020.

It is important to remember that as with many companies in our space, we expect our Q1 gross to net to be higher due primarily to the coverage gap as a result of the benefit reset at the beginning of the calendar year. Cost of product revenues for the full year was $24.2 million. The gross margin was approximately 82% for the year.

It is important to note that our gross margin benefited in 2019 from inventory expense prior to the FDA approval of ARIKAYCE and this will not continue at the same rate in 2020. Turning to expenses. For the full year 2019, research and development expenses were $131.7 million. SG&A expenses were $210.8 million for the full year of 2019.

Our operating expenses for 2019 were $347.5 million, compared to $314.8 million in 2018. Our adjusted operating expenses for the year were $300.1 million versus $283.7 million in 2018.

We define adjusted operating expense in our earnings press release as GAAP operating expenses excluding stock-based compensation expenses, depreciation, amortization of intangibles, and a milestone owed to the CF Foundation related to ARIKAYCE.

For 2020, we will continue to invest in our core operating business, which includes continued commercialization of ARIKAYCE, global expansion activities in both Europe and Japan, and pipeline of assets. In addition, we will begin to invest in the preparation for the planned Phase 3 programs for INS1007.

Consequently, we expect adjusted operating expenses for 2020 to be in the range of $340 million to $360 million. We ended the year with a strong cash position of $487.4 million. It is important to highlight our ending cash position is in line with our ending cash position as of December 2018.

We believe this illustrates our ability to maintain a strong balance sheet where we manage appropriate development investment with responsible financing and revenue. We will continue to remain disciplined and judicious with investments in our business and conscious of preserving our capital in order to maintain a strong balance sheet.

With that, let me turn the call back to Will for closing remarks.

Will?.

Thank you, Sara. Let me close out our prepared remarks by reiterating that we are extremely proud of the continued execution by the team at Insmed. Our ongoing commercial efforts for ARIKAYCE continue to progress and we are creating a strong franchise with the potential for additional launches in Europe and Japan.

We are advancing our efforts to expand the market on moving forward studies in the frontline and EM obsesses settings. Behind ARIKAYCE, we are pursuing high value opportunities in the areas of unmet need.

With 1007, we have a unique and significant opportunity with a potential first-in-class therapy for bronchiectasis if we are successful with our Phase 3 program. We believe we are just scratching the surface of what we can achieve with this compound which we believe has significant potential in other disease states.

Moreover, our growing pipeline has strategic leverage with the advancement of 1009 and our newest candidate RV94. Taken together, we believe we have one of the strongest portfolios in the pulmonary rare disease space. I want to congratulate the Insmed team for a phenomenal 2019.

As we sit here at the beginning of 2020, we are very excited about what lies ahead for the company. With that, I’d like to open the call for questions.

Operator, can we take the first question please?.

[Operator Instructions] The first question today comes from Ritu Burrell of Cowen. Please go ahead. .

Good morning guys. Thanks for taking the questions.

Will, and team, can you talk a little bit more about the structure of the PRO? What modifications were made to the existing scale? And any more detail that you can give us on how the forward in Phase 3 powering assumptions and timeline for cohort data? At the end of the day, when can we feel more secure that you’ve got your handle around the PRO and how the PRO will behave in the Phase 3? And I have got a follow-up.

Thanks. .

Sure. I appreciate the question. So, let me just say, when we talk about the PRO and its developments, this is a process that began in sort of the middle of last year in earnest with the FDA. And so, we’ve had a lot of back and forth and I think I feel pretty good about where we are in that process.

There is a whole lot of effort in research that goes into making sure PRO is appropriate and works as expected. And we are well underway in the first part of that assessment which is making sure that it’s appropriate and that requires additional research.

We then confirmed that what we have to bring forward is something the FDA is comfortable with, and then we initiate the trial to validate that PRO.

The unique design of our post-approval requirement program contemplates that validation trial running in parallel to the full approval trial, as you’ve seen on the slide that was outlined today and was presented for the first time in JP Morgan.

So, for those reasons, we are awaiting the final sort of sign-off from FDA, but I don’t anticipate that will be problematic and my expectation is that this trial – both of those trials will begin in the second half of this year.

As far as the PRO itself, it’s made up of a modified QOLB questionnaire which is a Quality of Life Bronchiectasis questionnaire that was explicitly discussed with FDA and indeed they encouraged us to consider if we wanted to we thought it was appropriate using a modified existing questionnaire.

So I think we feel like, we are on very solid ground there.

What we hope to discern in the validation study is which of the specific questions and domains seem to have the greatest response rate in the patients that are being treated with our drug and with that information, we can then confirm the statistical analysis plan that outlines how we will test the efficacy of our drug using the PRO in the post-approval requirement study.

So, all of that is sort of framed out in the study design and we talked about it previously.

We’ve estimated and these are estimates somewhere in the neighborhood of 200 to 300 patients in the post-approval requirement study, those might move a little bit, but we don’t expect them to move massively, although, there is always more to be learned and we want to caveat then our dialogue with FDA is ongoing and may influence that a little bit.

But overall, I would tell you, I think we feel very good about the study design as we outlined in the comments. We expect it to run for a little over a year, 12 months on drug and then one month off. We expect this study to also be satisfactory using the primary endpoint of durable culture conversion for both Europe and Japan.

So if we fast-forward, the study kicks off in the second half of this year both run we have the outcome of that study and that’s to satisfy U.S., Europe and Japanese regulatory requirements securing for us frontline approval for this drug’s use in the treatment of NTM MAC and that increases the addressable market we are talking about in each of our territories by something north of five-fold.

So this is a massive opportunity and we want to make sure we get it right, but we are also as eager as the investment community to get it started. .

But how long does that validation study need to run before you feel like you’ve got a good handle on the PRO and the PRO powering?.

So, going into the study, I think we already feel like we have a good handle on that. We have a number of different sources of data that we use to inform the design of that study including some specifically with the newly designed PRO.

But we also have data from the non-CF bronchiectasis QOLB questionnaire that was administered during our Phase 2 program. We’ve looked at patients in other databases who have the refractory NTM. And I think the collective takeaway from all of that analysis is that, we think this PRO is going to be appropriate. We think we understand the powering.

And the way to think about that parallel study structure is that that will be confirmed before we read out the final result of the main lung study. And I think that is the point of greatest comfort at least for me when I look at the probability of success of that study.

We will have the PRO with a high-level of confidence and data directly relevant to our belief that it’s going to be effective in teasing out impact of ARIKAYCE.

But we will also be able to confirm that prior to the reveal of the Phase 4 post-approval requirement study and that will allow us the opportunity, because that study will still be blinded to make adjustments should we need to in that statistical analysis plan. .

Got it. And my follow-up is just on the low-end of the guidance, Sara that you mentioned today the $180 million to $220 million.

What was the calculus that went into the low-end? Is it sort of what if the guidance doesn’t work and patient starts slowdown and you are not effective in these last 3,000 prescribers? Or is it more of the contracting the increasing and the increasing gross to net? And maybe one last one. .

So, I appreciate that question, Ritu. And obviously, we spend a lot of time thinking about this. I would define the year 2020 as being marked by both uncertainty and opportunity.

The uncertainty that surrounds the performance of some of the key metrics as we go forward, it’s the same kind of uncertainty that was frustratingly experienced last year where we struggled to really be able to discern where the commercial launch was going to go.

Because no one has ever launched in this disease state and the performance and use of this drug is still yet to be fully defined. If we revisit the guideline-based treatment of the patients using our drug, it would contemplate treatment to culture conversion plus an additional 12 months.

So we are just at the front-end of patients defining what that full duration of use is and that’s a really important and uncertain metric as we move forward. It’s not the only one. But it’s an important one and I think we want to acknowledge that we still don’t know how that’s going to unfold.

We have some perspective on it and we have every reason to be confident that we will be able to deliver in 2020 as we did in 2019. But it would be imprudent in my judgment to not acknowledge some of the uncertainty. Offsetting that I think are the significant opportunities that Roger outlined.

The arrival of a paper that peer reviewed that talks about how to use ARIKAYCE and minimize side-effects. The arrival of treatment guidelines that will reinforce appropriate duration of use.

These sorts of things and some other accretive programs that I know the commercial team are working on to really continue to take advantage of what we believe to be that remaining patient and physician population that have not chosen to use ARIKAYCE yet.

But at the heart of your question, is that the uncertainty of the metrics that are driving use of drug or is it lack of confidence in the access to patients and physicians? It is absolutely the former not the latter. And I don’t know, Roger, if you want to add any additional clarity to that..

Yes, thanks, Will. I do want to reiterate, first of all, we’ve had incredibly strong performance from ARIKAYCE and from our team executing through the launch and the U.S. commercialization. And fundamentally, I think our franchise is strong. We continue to receive positive feedback from physicians and from patients who are experiencing ARIKAYCE.

But we know that there is a very strong propensity to prescribe ARIKAYCE for the refractory patients.

I think, in addition, we talked about the number of catalysts and also the uncertainty around the variable for how long patients going to receive therapy and maybe a good way to think about this, I know we’ve shared this metric on the previous call, we talked about for those patients that cohort of patients who started in the fourth quarter of 2018, which was our first quarter of launch.

The patients who have had the longest exposure or potential exposure to ARIKAYCE, we had reported that as of the end of the third quarter of 2019, for those patients who have made in to at least months forward, so made in through those first 90 days, that 80% of those patients were still on therapy at the end of the third quarter of 2019.

So, we continue to track that cohort and surely over time, that cohort will become less meaningful as we get more experienced with a much larger group of patients. But an update on that specific Q4 cohort again for the patients who make it at least a month forward, we see 60% of those patients were still on therapy at the end of 2019.

So, initiated therapy in the fourth quarter of 2018. 60% of those patients who made it to month four still on therapy at the end of the year, we think that’s an encouraging metric. And we will continue to track this and look at duration of therapy. That’s our key variable.

This is just – as we have mentioned there is some uncertainty around that that will have a significant influence on ARIKAYCE moving forward.

One of the good reasons why we were anxiously awaiting to the guidelines is that opportunity to reinforce the duration of therapy for physicians, obviously, the KLOs understand, there is a sense of excellence to understand this, the opportunity will be to reinforce that duration and the appropriate refractory treatment for physicians in the community setting.

.

And I would just close by saying, we’ve faced some of this uncertainty last year and I think we performed incredibly well. My confidence in the commercial team is not abated in any way.

In fact, if I could give one piece of insight to all the research analyst and investors on the phone, it would be the degree of energy and enthusiasm that exists within Insmed today.

We are in as strong a position as we have ever been in terms of our enthusiasm for both the ARIKAYCE opportunity and the potential of our pipeline including 1007, 1009, and RV94 among other things. So, we entered 2020 with a very positive sense of momentum and direction.

And we’ll see how that plays out and we certainly will update you as the year goes on. .

Great. Thanks for taking all the questions. .

Of course. .

The next question today comes from Matthew Harrison of Morgan Stanley. Please go ahead. .

Great. Good morning. Thanks for taking the questions. I guess, first one, just maybe on the guidance again.

Can you be – to the extent you can maybe just provide a little bit more clarity in terms of how you think some of the factors that you highlighted in terms of gross to net and COGS and some of those other things are going to sort of move throughout the year? I know you gave us a broad view, but maybe you could give us a little bit clear view around how much you think 1Q is going to be impacted? And do you expect that donut hole to be a bigger impact this year? And then I have a follow-up.

Thanks. .

Yes, so, I’ll just frame out at the outset. I think, we did call out the donut hole’s impact is being more magnified this year. That is absolutely the case. There is nothing we can do about it. It is a feature of products like ours in the Medicare populations that that donut hole pinches in January every year and certainly we saw that this year.

However, I feel the rest of the year before us and in the early part of February that is a temporal event, seasonal effect, if you will.

And so, it is for all intents and purposes behind us, I think our attention now turns to taking advantage of the opportunities that present themselves in terms of some of the things we just mentioned in the script and during the last question response.

On the specifics of gross to net, and gross margin, I’ll just ask Sara to comment on what our guidance is for the year. We obviously don’t have any more details, but maybe to frame out those metrics. .

Absolutely. Thanks, Will, and thanks, Matthew for your support and for your great questions. So on gross to net, as we seen it full year 2019 was approximately 10%. We anticipate 2020 to be in the mid-teens.

Q1 will be higher and on average for the year, we anticipate it to be in the mid-teens primarily related to the change year-over-year primarily related to some of the contracting and pricing that’s still favorable gross to net. On COGS, we obviously had previously expensed material in 2019, which we were able to benefit from.

We had a gross margin of about 82%. We will not see that same level of benefit into 2020. But we are also very cognizant of keeping our COGS at appropriate levels. So hopefully that provides a little more color for you. .

Okay. Thanks. And then, follow-up.

Just on the guidelines, maybe just your current expectations around when we see them?.

Yes, this is one of our favorite questions. We were told by the Chair of the Guidelines Committee at year end of last year that they would be outside the end of the year. Here we sit at the beginning of the next year awaiting their arrival.

Everything we hear and of course we are not directly involved with the committee, but everything we hear from them is that they are imminently forthcoming. I was encouraged to see an explicit session called out in the agenda for the American Thoracic Society Meeting, where they will be discussed and reviewed.

So I think that portends their imminent arrival and I think the sooner they come out, the sooner we can take advantage of them. I will say that I am confident that they are coming out. And that when they do come out, these will be a force that will benefit us for not just the immediate term, but over the course of the next several years.

They will be the feature of discussion at American Thoracic Society, European Respiratory Society and Infectious Disease Society of America and CHEST. And I highlight within that group, the European Respiratory Society, because these guidelines will not just be coming from U.S. societies. But their European counterparts as well.

So it’s conceivable that when they are issued the European societies will have endorsed the use of ARIKAYCE for the treatment of refractory patients, prior to their approval by EMA. And I think that’s a strong statement if indeed that ends up being the case of the appropriate potential for this compound for those patients. .

Okay. Thanks. .

The next question comes from Martin Auster of Credit Suisse. Please go ahead..

Hi, this is Mark on for Marty. Thanks for the comprehensive update today and for taking my questions. I guess, first, maybe a little different with respect to guidance, but getting out the same question.

I am curious from your interaction with doctors, what’s the actual script duration including refills that they are typically prescribing to patients? And then, my second question is, with respect to 1007 and thinking about the dose response, was there a higher rate of exacerbations relative to the rest of the trial population and those that had periodontal disease? Thank you.

.

I appreciate the questions. On the first question, what is the duration of use that we are seeing from hearing about from physicians? What I would say generally is that, the physician community we hear from is very much a proponent of treating to guidelines.

And so that would suggest that they will treat to culture conversion and that that for an additional 12 months. There are a variety of physician perspectives on this. I’ve heard some physicians who feel that they’ve seen benefit with their patients on drug and intend to keep them on the drug longer.

I’ve also heard of physicians who have patients that treat patients for a period of time. They have some success.

The patient wants to go off-drug and what’s interesting about that patient and this is one of the big uncertainties and opportunities in 2020 and really 2021 is that we know the reinfection rates in these patients are extremely high particularly in refractory patients.

And so, it would be my expectation and many of the physicians’ expectations that these patients are going to show up and require re-treatments and the question before us that is uncertain is, how soon will that patient be identified once they are reinfected? How quick is the physician inclined to re-treat with ARIKAYCE given that that’s refractory patients and when will we begin to see those patients come back into the top of the funnel, if you will.

So, that’s my perspective. I don’t know, Roger, if you want to add anything to the duration. .

Sure. Thanks a lot. I am happy to. So I think that the question is really along what’s the intent for the physician to prescribe. And I would agree with what those saying is that, large part of the physicians’ intention is to prescribe according to the guidelines, as treat to conversion plus another 12 months.

They also are encouraged, I think for a check-in at six months and if patients haven’t converted to make that assessment as to whether not to continue therapy or not.

And we shared that previous, the metric around the fourth quarter 2018 cohort of patients and the 60% of those patients a year after initiating therapy are still on therapy as of the end of the year. So we think that that’s encouraging and to support that, we mentioned that real authorizations have not been an issue for us today.

And so, while the insurance companies have been obviously were looking for the appropriate patients will be starting on therapy, they really are looking for the judgment of the physician as to whether continue to – to continue those patients on therapy.

And so, we think that that’s encouraging metric and the guideline opportunity will give us an opportunity to reinforce that duration of therapy with physicians and reinforce what we think is the practice largely at this point. .

And I guess, I would just say, also, we are aware of the lot of the surveys that some of the research and investment community have done. We heard of the inputs from those.

Those are not inconsistent with our experience and what we heard, I think our guidance reflects what we believe to be the existence of some uncertainty as we have always tried to transparently convey to the investment community. But it should not be interpreted that we have an insecurity.

I think it is a matching of uncertainty with opportunity and our ambition to go out and address those opportunities in a way that will benefit patients and ultimately therefore our shareholders. On the second question with regard to 1007, I’ll ask Gene to address that. .

Sure. Thanks. Yes, and so this was a question about periodontal findings and maybe correlations with efficacy and I think that’s a really interesting question. I can say at the outset, I don’t have a direct answer for you at that time. This is the type of analysis we want to conduct.

I think, from a big picture standpoint, the events that we saw in that our periodontal were mild to moderate and some of the work that we are going to do is try to understand to what extent these were spontaneous events that were reported by patients and to what extent actually they were elicited by having these dental exams.

So I think, it’s like Heisenberg thing. Because we were looking at it, we may have detected more than we otherwise would had we not had those periodontal dental exams. So that’s an aspect we want to look at.

But certainly, understanding whether patients who seem to have some type of periodontal manifestation are those the ones that got the most efficacy. So that will be an interesting question. I think along those lines, we are also going to look at exposure response for both safety and efficacy.

So, are the patients who have the highest exposure, tend to be the ones who have the most efficacy and that that correlates with any of the safety filing. So, that’s the type of work we really want to delve into. I don’t have answers for you today. I think it’s really important that we look closely at it.

So that we really fully understand the effects both from a safety and efficacy side, as we make decisions about Phase 3. .

And the only thing I would add to that is that, as of right now, it’s not our expectation that that’s kind of periodontal exam using a dentist what we required for Phase 3 which I think speaks to the preliminary takeaways of the Phase 2 data assessment in that regard. .

Thank you. .

[Operator Instructions] The next question today comes from Adam Walsh of Stifel. Please go ahead. .

Hey everybody. Thanks for taking my questions and congrats on all the recent success. So, my first question is, I am trying to get a little better handle on the duration in reinfection. And I don’t want to beat a dead horse.

But Roger, you said previously that 60% of the patients that started on original therapy, at approval, we are still on the drug at year-end 2020.

And I guess, my question, do we have any information as to why the 40% came off? What the average duration of therapy that they were on prior to coming off? And whether or not those patients could be mischaracterized as just drug holiday patients as we’ve heard a lot of docs say, I’ve been using drug holidays to temporarily pause the medication and keep them on for longer period of time.

And then, finally have any of those patients that have come off reemerged for reinfections? In other words, what do we know about reinfections at this point in time? Thanks. .

Hi, Adam. Thanks for the question. And certainly, as you are trying to get your arms around that, we are certainly doing the same thing and we don’t have perfect information or insight, as I am sure you can appreciate.

You are right, with the metrics, so the 60% of the patients who made it to month four in that Q4 2018 cohort were still on therapy at the end of 2019. We think that’s a very encouraging number. What happened to that other 40%? We don’t have, again perfect insight there, but it’s a mixture of things.

So, there are patients who are assessed to have completed therapy. There are patients who decided that they no longer wanted to continue with therapy and again this is just feedback anecdotally that we are getting through especially pharmacies, through our Arikares network.

I would say, it’s completely not drug holidays necessarily unless you think about patients who may have – and to your point, the reinfection, they may have stopped prematurely with and certainly at this point, they would not have had the additional 12 months of therapy that the guidelines recommends we’ve shown you eradicated that disease.

So it’s not unreasonable in that case to think about reinfections popping up. I’d say it’s too early at this stage to comment on reinfections. But we know that from both the literature and we would expect in the real world setting, that you will see some of these patients returning with a new infection and will need to retreated.

And importantly I think having a positive experience with Arikares, physicians, journalists have reported to us that they would be very happy to initiate ARIKAYCE for those patients once again if there is that reinfection. .

Great. And then, just another one if I could. On the guidelines, we talked a little bit about the potential kind of acute and longer term benefit. Roger, you mentioned that you have 3,000 physician targets left still to kind of hit.

And how quickly do you think the guidelines might have an impact on that broader pulmonary community that maybe isn’t as familiar with how to use the drug at this point. So the acute aspect, how kind of impactful do you think that could be, maybe over the course of the next four to six quarters? Thank you. .

Yes, thanks, Adam. So, I think, we’ve looked at this as long as we looked at a President and I think that there is a variety of different impacts that we see as that might informed us. So, I think it has had a specific guess as to what that looks like.

But for us, I mean, anecdotally and what we think we can do with this commercial team having those guidelines, we think that will have positive impact.

There is – like you said, the 3,000 physicians that have not yet written their prescription for ARIKAYCE, our impression is, it’s not that they don’t have that positive perspective, but they are looking for reinforcement and the right refractory patients who are suitable for ARIKAYCE.

These guidelines will give us that opportunity to reinforce that, looking at all of the literature, this is how you define a refractory patient and this is what the appropriate therapy is according to the medical societies.

And I think that that’s a very powerful message for us to supplement the great efforts that we have from an education and promotional effort within our commercial and medical teams. .

Thank you. .

The next question today comes from Graig Suvannavejh of Goldman Sachs. Please go ahead. .

Yes. Thanks. Good morning. Thanks for taking my questions. I’ve got two and my apologies if they may have been asked before.

Maybe my first question just has to do with the outstanding physicians who have yet to use ARIKAYCE? And maybe can you just your interpretation or your color as to what ARIKAYCE having been on the market for some time? Why they have yet to use ARIKAYCE? And then, my second question, congrats on the recent additions to the management team and senior leadership.

In terms of your new BD hire, can you just give us a sense kind of as you look into 2020 and beyond.

And having added a pipeline asset which is very new, but what kind of deals are we looking for on a go-forward basis in terms of what their in-licensing opportunities, like, Speedy partnering? Out-licensing opportunities? Any color would be great there. Thank you. .

Sure. I appreciate the questions. I’ll ask Roger to address the first one. .

Yes, thanks. So, I think, it’s a great question around the – why we haven’t seen all the physicians prescribe ARIKAYCE at this point. And I would say, that as we are thinking about the tail and we are thinking about those 3,000 physicians, there is a couple of factors. First of all, the propensity to prescribe remains very strong.

So when we do have market research and we talk to physicians across the board, their intent to use ARIKAYCE in the appropriate patient is very strong. So, that leads us to believe that it’s identifying that appropriate refractory patient.

And this is a rare disease, I will remind everybody a rare disease we made the strategic decision to go more broadly to the community and these physicians don’t see these patients every day. So they do come in periodically. We know that those patients are there.

And so, it’s an opportunity for us to reinforce how to identify those refractory patients for NTM and to reinforce with them that these patients haven’t converted after that standard-of-care treatment, you should be thinking, considering adding ARIKAYCE to that regimen. And so, it’s fundamentally, in our opinion, nothing more than that.

It’s raising that awareness, reminding them with when those patients come into assess the culture status and make that decision as to introduce ARIKAYCE to their appropriate refractory patients The propensity to prescribe familiarity with ARIKAYCE is very positive..

And on the second question, you asked about the BD hire and I think there the intention was simply to bring in somebody who has a great deal of experience that can help us formulize what has been a very active business development effort in the 7.5 years that I’ve been here. We looked at literally, well over a 100 opportunities.

You’ve seen the 1007 results and I think they speak to the ability of the team to discern what is a promising program and present some real arbitrage for our investors while we are out in pursuit of a therapy that maybe able to benefit patients if it clears all the regulatory and clinical hurdles.

I’d like to repeat that and I’d like that to be in a very systematic fashion. But our hurdle is high. It remains high. And we are very cognizant of the scope of the development that we are taking on in terms of these various programs.

And so, I think, if I were to frame out what we be looking at, my ambition would be to look at either the commercial end of the spectrum and see how we can really build off of the tremendous success that the commercial team has already established or indeed, something that could be complementary to where we are already pursuing programs.

I will say that, we view ourselves as a rare disease company and so we don’t feel restricted to the pulmonary rare space. We happen to be have a lot of overlapping products and programs there that I think are going to complement one another extremely well and allow us to get a lot of leverage around the world as we build out.

But we don’t feel exclusively restricted to that. We think where patients are particularly challenged, where there isn’t a lot of competition and where we have the ability to go in and help on the education front. That’s probably where we can have the greatest impact and Fred’s arrival heralds a real formal approach to that.

But it’s not inconsistent with what we’ve been doing today. .

Okay. Thank you very much. .

And our last question today comes from Liisa Bayko of JMP. Please go ahead. .

Hi, there. Thanks for taking my questions. I wanted to ask a little bit more about kind of your next steps for 007. So, is there any situation where there is a faster market strategy here? And I ask that just because the data, the quality of the data and the unmet medical need in that setting of bronchiectasis.

Just curious if there is any faster market strategy or something where you parallel path to the Phase 3?.

Yes. I appreciate the question, Liisa, I think, look, we share your enthusiasm for 1007 and all that that represents. Our next step here is to talk to the agency about where we go from here. We have a design already prepared for Phase 3. It contemplates to trials and it contemplates at this moment two doses.

More to be learned once we have that interaction with the regulatory agencies around the world and I think in order for those interactions to be productive, we have to complete our detailed analysis of the data. And that's something that's underway at the moment.

Who is to say what the path will be, I am just framing out our base case expectations and if I we learn more or see additional opportunities, we will certainly share those. .

Okay. So, you just kind of give a little preview to my next question was just really around, I guess, thinking about the trial design? You talked a little bit about that. Any more color? What about duration? When do you think you might start? How long do you think it might take to recruit? I am assuming you have global studies.

Maybe give us a little more color, so we can start to think about what the timing in terms of getting that remarks?.

Yes. So, we were ready for the lottery ticket as I described it to go the right way. We have two designs prepared. We have it as a corporate goal to start these studies by the end of this year. That will be subject to our interaction with regulatory authorities.

We expect the studies to each would be one year in length which has been the history of non-CF bronch development. And so, that’s as much as we know at this time. When we talk about numbers of patients in the studies et cetera, that’s more work I think we want to refine before we come back.

But I would believe given the enthusiasm of the community that these will enroll relatively quickly and that they will be studies that will satisfy approval in multiple territories around the world. And I think that is an extremely exciting opportunity. DPP1 Is now a very strong set of data out there validating.

It is a mechanism of action and that is changing the equation for how people think about this mechanism, not just for bronchiectasis, but for other diseases, as well. .

And then, when would you be prepared or what’s the – maybe you can give us a little bit more granularity on timing of looking at this molecule in the some of the ones you mentioned CF at a alpha antitrypsin and those kind of other diseases?.

Yes, so some of that work has already been done. Quite frankly, we did some animal model work in a couple of these other disease states. We think there is more to be done, particularly in light of the learnings from the Phase 2 program. So that will be ongoing this year and I think it will inform where we go next and how we do that. .

Okay. And then just final question for me, RV94, interesting molecule, maybe you can talk a little bit more about where that came from? And then how is that different from the compound that Savara has also in development for MRSA infection in the lung? Thank you. .

Sure. That compound is from our own labs, much like ARIKAYCE, we developed it internally. Incredibly, a capable group of people and we have lot of stuff going on, but it gets to ready for primetime then we bring it forward. RV94 we think it means that threshold.

I’ll let Gene comment on how it differs from the compound you are talking about over Savara which is the Vancomycin and held vancomycin, and some of the metrics that we outlined today. .

Sure. Thanks. Yes, I mean, we think that in general the hypothesis at treating MRSA in CF patients may improve outcomes is a very reasonable hypothesis. We thought that vancomycin may not be the right drug for it though.

So, Walter Perkins and his group in our research group, spent quite some time looking at a number of different compounds, novel compounds for two of the characteristics. One is potency against MRSA and the other is lung kinetic. So, the retention time in the lung.

And so, we spent a quite a – we went through a quite a number of different compounds trying to optimize that. And clearly, superior agent was this RV94, which in various in vitro the testing is clearly more potent, significantly more potent than vancomycin in both in vitro.

I have mentioned the MIC assays, we have biofilm assays in which it outperforms vancomycin and other, even the related lipopeptide drugs and also in animal models of MRSA. So, we think it’s – my thought of it is, that this is a reasonable thing to attack and we think we have a very strong candidate in RV94.

It is early and we have a lot more work to do on it. But it is very exciting..

And then, let me just comment, maybe given the scope of what we talked about from a development point of view here, when we talk about RV94, when we talk about 1009, there are – and 1007, these are compounds that may apply into creative ways to get funded as we go through the development process.

So, RV94 is an example as one that may be able to benefit foundation support given that it has a potentially primary role to play and if it continues to perform as it has.

We look at 1009 and we think of that as entering a fairly competitive market, but with disease modifying possibilities, that drug represents a potential source of development for us or for others in a partnership. And we’ve seen reasonably how disease modifying agents in PAH have been valued.

And finally, 1007, while we intend to bring it forward in bronchiectasis in the various territories around the world, we also think potentially about its role in a place like China, which is a prevalence rate is – as we understand it of bronchiectasis is about 10-folds greater than what it is in U.S.

So it’s quite a significant opportunity and we are going to think very creatively about how we might be able to offset some of the development costs for these various programs in a way that allows them to progress, but doesn’t necessarily a result in endless cycle of need for additional equity issuance.

And I think that’s an important point for people to digest. Bottom-line, I was asked by a couple of portfolio managers with the result of 1007, which we described in the lottery ticket, did we have other lottery tickets at Insmed and that’s why today we’ve decided to draw attention to 1009 and RV94, both of which I think fall into that category. .

Okay. Thanks. A lot go in the pipeline. I appreciate the updates. Take care. .

You bet. .

This concludes our question and answer session. I would like to turn the conference back over to Will Lewis for any closing remarks. .

Thank you all very much for joining us today. .

The conference is now concluded. Thank you for attending today's presentation. You may now disconnect..