Welcome to the Vertex Full Year and Fourth Quarter 2018 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Tonight, we will review our continued efforts to develop new medicines for all people with cystic fibrosis, recent advances in our research and development pipeline, and our 2018 financial results and 2019 guidance. Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer and I would like to welcome to the call Paul Silva, Vertex’s Interim Chief Financial Officer. Paul has been Vertex’s Corporate Controller and Chief Accounting Officer since 2008. And he and his team have worked closely with the Investor Relations Group since that time. Following prepared remarks from Jeff, Stewart and Paul, Dr. Reshma Kewalramani, Chief Medical Officer will join us for Q&A. We recommend that you access the webcast slides on our website as you listen to this call. The conference call is being recorded and a replay will be on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today’s press release and our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex’s marketed CF medicines, the ongoing development and potential commercialization of our triple combination regimens for cystic fibrosis, Vertex’s other programs and Vertex’s future financial performance are based on management’s current assumptions. Actual outcomes and events could differ materially. I will now turn the call over to Dr. Jeff Leiden.

Thanks, Michael. Good evening, everyone. Over the past several years, I have shared with you Vertex’s strategy to create multiple transformative medicines for different serious diseases by continuing to leverage our long track record of serial innovation. I am pleased to review with you this evening the significant progress we made in 2018 on executing the strategy and to discuss the important growth drivers that we expect in 2019, which will include many important clinical, reimbursement and commercial milestones and CF as well as clinical data from across our research and development pipeline. In CF, we expect to obtain the Phase 3 data for the VX-445 triple combination this quarter and remain on track to submit a new drug application for a triple combination regimen no later than midyear. We also expect to see more patients initiating treatment with our medicines throughout 2019. As a result of global label expansions and from key reimbursement agreements reaching 2018, which will drive further revenue growth this year. In our non-CF pipeline, data expected in the first half of 2019 from our Phase 2b dose ranging study of VX-150 will inform our plans for potential Phase 3 development in pain. In our AAT program, we are advancing a portfolio of small molecule correctors, including our first molecule and entered Phase 1 development in late 2018 and a second that is expected to enter clinical development this year. And in sickle cell disease and beta thalassemia, we have now initiated enrollment of both of our Phase 1/2 studies of the gene editing treatment of CTX001. I will briefly review each of these pipeline programs with you this evening. First to cystic fibrosis, today approximately half of all people with CF are eligible for a Vertex CF medicine. And we stand on the verge of…

Thanks, Jeff. I am pleased to review with you this evening, our strong commercial performance for 2018 driven by the launch of SYMDEKO in the U.S., and also our revenue guidance for 2019, which shows continued revenue growth as we treat more patients with our approved medicines globally. Approximately, 18,000 patients are currently being treated with our CF medicines and this resulted in CF product revenues of $868 million in the fourth quarter. The fourth quarter included $294 million in revenues from SYMDEKO in the U.S., which was the primary driver of the significant growth in CF revenues in the quarter and throughout 2018. Our full year 2018 CF revenues were $3.04 billion, a 40% increase compared to the $2.17 billion for 2017, which is a direct result of treating many more patients globally. In the U.S., we saw a large number of patients initiate and remain on treatment with SYMDEKO in 2018. Demand for SYMDEKO has come from all eligible groups of patients including those who previously discontinued or never initiated ORKAMBI and those who switched from ORKAMBI or KALYDECO to SYMDEKO. Given the profile of SYMDEKO, we had expected that persistence and compliance rates might be greater than those seen previously with ORKAMBI. And we are pleased to see this play out in the real world. While we are now well into the launch of SYMDEKO, we do anticipate additional patients will initiate treatment throughout 2019, including patients’ ages 12 years and older as well as younger patients following potential approval in children ages 6 to 11, which we anticipate during 2019 and is reflected in the guidance I will discuss in a moment. KALYDECO revenues for 2018 were $1.01 billion, an increase of 19% compared to 2017. The increasing KALYDECO revenues, is a direct result of treating…

Thanks, Stuart and good evening everyone. Vertex’s financial performance in 2018 was marked by 40% growth in CF revenues coupled with disciplined investment into our business, which drove significant increases in our operating margins, operating income and cash flow. In addition to Stuart’s comments on 2018 revenues and 2019 revenue guidance, I will provide additional remarks this evening regarding our 2018 financial results. I will also discuss our 2019 financial guidance for R&D and SG&A expenses and for our effective tax rate. All of the results and guidance that I will discuss are non-GAAP. As Stuart noted, we saw a significant increase in CF product revenues driven primarily by the launch of SYMDEKO in the U.S. KALYDECO label expansions also contributed to the revenue growth in 2018, where KALYDECO revenues reached $1 billion for the first time since its approval in 2012. This underscores both the important role that KALYDECO plays in the lives of thousands of patients around the globe and the continued strong demand for the medicine as we expand its label to new and younger patients. Our fourth quarter 2018 combined R&D and SG&A expenses were $400 million compared to $355 million in the fourth quarter of 2017. Our full year 2018 R&D and SG&A expenses were $1.53 billion compared to $1.33 billion for 2017. The increase in these expenses was primarily due to the advancement of our portfolio of triple combination regimens and investment to support the use of our medicines globally. The significant growth in CF revenues in 2018 resulted in fully year operating margins of 37% compared to 26% for 2017 as well as operating income of $1.11 billion, a 97% increase compared to 2017. Net income for the fourth quarter of 2018 was $337 million compared to $158 million in 2017. Our full…

Thanks, Paul. In closing, 2018 was a highly successful year of commercial and clinical execution across our business. Our achievements over recent months have positioned us for continued growth in revenue and operating income in 2019 and beyond and for important near-term milestones across our R&D portfolio both in CF and in other diseases. Our strategy of creating transformative medicines through serial innovation is working exceptionally well as evidenced by the rapid progress seen across our business. And I look forward to updating you over the coming year. With that, I will open the line to questions.

Thank you. [Operator Instructions] Our first question comes from Michael Yee of Jefferies. Your line is open.

Hey, thanks for the question and congrats on a great quarter. Two topics I thought you could address. One is giving the Street some comfort about obviously what’s been in the news recently that UK and more broadly speaking the confidence that, that region will work itself out and to be specific whether to say safe better pharmacoeconomic value drug will help solve that equation? And the second question is a pipeline question you talk very nicely about AAT you did say there is a second one coming in. Are those combinable, are they similar, just more potent, maybe talk to how having two connections better than one or maybe I am getting ahead of myself? Thanks so much.

Hey, Mike. It’s Stuart. I will take the first question on the UK. I mean, before I go on to the UK, I do want to reference we made great progress from a reimbursement point of view in 2018 and that’s reflected in the results we were able to share with you today, important agreements in places like Australia and Sweden and Denmark. Last year and we have continued that momentum into 2019 where we have secured new agreements in places like Israel and Luxembourg and the pricing agreement for ORKAMBI for 6 to 11 year old kids in Germany. So, we continue to make great progress getting access for patients around the world. Where we have been successful in large part is due to those countries using what we would consider to be appropriate methodologies to assess the value of these unique and transformative medicines and because our goal is to get access for real eligible patients we are continuing to pursue that with every bit of energy we can in the UK. I think it’s important to split the UK up as you have probably known Mike from a healthcare perspective, the UK is managed and a developed country, so each country had its own process. So in Scotland, we have made great progress. We have reached an agreement with them about how they are going to assess our medicines and we have submitted on the verge of submitting ORKAMBI and SYMKEVI to the Scottish government and we are optimistic we will get access there hopefully in 2019. In England unfortunately, we are yet to reach an agreement with them on what we would consider to be an appropriate methodology, but we are certainly not going to give up on that. We are going to continue to fight to get access for patients in England as we have for patients around the rest of the world. The last thing I will say to you is that we know what the results will look like even if we put the triple combination regimen through the existing nice methodology, even if the results are as good as we saw with 659 in the Phase 3 study that we released in November. And even those results when put into the nice model don’t come out with a valuation which we think in anyway gets close to valuing the transformative nature of these medicines. So even for the triple, we are going to continue to need to work with England to change the assessment methodology for all medicines.

Okay.

On the AAT question, I think I will hand over to Jeff.

Hi, Mike, it’s Jeff. Thanks for the question on AAT. In many ways, I think you can think of this as a very important lesson that we learned from our CFTR next-gen program right and we sort of had the saying Vertex crack the biology then pour on the chemistry. We believe we have cracked the biology of AAT. We have multiple correctors that can reform the protein and causes to be secreted from liver cells in a functional form. And so we started following on the chemistry about a year and a half ago and to create multiple molecules. And the reasoning is just that our experience as with the CFTR next-gen Vertex’s as they get better and better and we like to take more than one molecule into the clinic because it’s a portfolio risk mitigation strategy if you will. And obviously these molecules have are predominantly efficacious, they have that the right [indiscernible] and just the right drug protein and action that can be tolerable. And so, our strategy with AAT and frankly with most of the programs, CF is going forward is going to be the pour the chemistry on create multiple molecules. Bring those forward in the clinic and compare them in early small cells and we’ve get a pretty quick idea of which are the best molecules. And so, these 280 molecules we don’t think of them, added and we really think of them as different molecules that we’re going to compare and by the way we shouldn’t be surprised to see us putting a third one forward as well because as I said, we just continue to get sort of better and better properties.

Got it. Thank you so much.

Thank you. Our next question comes from Geoffrey Porges of Leerink. Your lines are open.

Thank you very much for taking my question and congratulations also on the great results. First, of the 18,000 patients, could you give us a sense of how many come from the U.S. and ideally, how many come from Europe? And secondly could you give us the breakdown for KALYDECO, ORKAMBI and SYMDEKO by the main geographies. And then just a question for you Paul, are you comfortable that we should model that 21% to 22% tax rate in our models going forward beyond 2019. I think that’s what you suggest. I want to be clear about that.

Yes, it’s Stuart. I will take the first couple of questions there of the 18,000 patients who are actually being treated now it’s about two-thirds in the U.S. and about one-third ex-U.S. In terms of the breakout of the geographies in terms of the products for Q4 for our Q4 revenues the KALYDECO of the U.S. was a $160.0 million, ex-US was $95 million. For ORKAMBI, the U.S. was $225 million and ex-U.S. was $90 million. And SYMDEKO in U.S., it was $286 million and ex-U.S. was $8 million largely reflecting the launch that we just began to execute in Germany. So that’s the breakout for the quarter, if you want to have that annual ones, I’d be happy to catch up with you after the call.

Thanks very much.

Hi, Jeff, it’s Paul. Thanks for the question. And I’m going to give a little bit more detailed in your specific question, just to kind of let you know how we’re thinking about taxes. So, in 2019, we expect the effective tax rate to be 21% or 22% for the full year. And it’s primarily driven by a non-cash U.S. federal tax provision. And in future years, we expect that the rate could actually go lower due to geographic mix of income as our revenues continue to grow and our business advances globally. I’m not going to actually be able to give you what that rate is until we kind of get visibility of reimbursement in Europe. And then the other point I just want to make for everyone is that the majority of the guidance on the effective tax rate is non-cash and we expect to pay only approximately $25 million of cash taxes in 2019 compared to the $16 million that we’re going to pay in 2018.

Great. Thanks very much, Paul.

Thank you. Our next question comes from Phil Nadeau from Cowen and Company. Your line is now open.

Good afternoon and thanks for taking my questions. Just a couple on revenue growth drivers, so in 2019 guidance, could you give us some sense of how much of the revenue growth is coming from existing geographies with existing labels and versus how much is coming from label expansions that you expect to get in 2019? And then second question on the portfolio agreements that you referenced. Can you remind us which country is currently have portfolio agreements and how you go about negotiating portfolio agreements in the additional territories? Do you have to wait for an approval or is it something you can do proactively before for example the triples are approved? Thanks.

Yes, so I’ll take both of those. So in terms of the 2019 guidance that reflects really three things. One is, the sort of analyzing of the SYMDEKO launch in the U.S. into ’19 also the annualized effect of the label expansions we saw that both KALYDECO and ORKAMBI in 2018 and a contribution from countries where we were able to achieve new reimbursement agreements in 2018. In 2019, we are not expecting a large contribution from new launches because we don’t have as many of those in 2019, probably the most notable that we are assuming within our guidance is to be SYMDEKO in patients ages six to 11 and so that would be a new label expansion there. But the vast majority of it is coming from patients for whom we are label to get today. Just like to reiterate as well, it also assumes only revenues in geographies where we have reimbursement agreements today. If we were able to get significant new reimbursement agreements in 2019 and if they were material, then we would potentially have an upside to our revenue with update our guidance at that time. Until, the rich companies have portfolio agreements, if you see long portfolio agreement, you’ve seen one portfolio agreement Phil. So, it would be difficult to describe the more, but we have them for instance in places like Ireland, we have an agreement in Australia where we have a path to getting SYMDEKO reimbursed, when it’s approved by the TGA. Denmark, the Netherlands and so there is a number of different portfolio agreements that they are all slightly different. In terms of do we need to have regulatory approvals to get portfolio agreements again that varies country by country. But actually many countries are well aware of how quickly our portfolio is advancing and how impressive the results look for our triple combination regimens and so there is a significant interest from governments to be looking at these portfolio agreements even in advance of regulatory approval. Indeed, one of the countries, we are talking about early on, England has been one of those markets that’s expressed an interest in those portfolio agreements. And remember that, the key to those is that win, win, win for us, but patients and for the government. The win for us is, that we would like to be able to have reimbursement agreements which kick in as soon as regulatory approval has been agreed. There are wins that physicians and patients who could get to choose the best Vertex medicine as sooner they approved and there is a win for governments because they give them a level of budgets during treating in CF patients.

That’s helpful. Maybe just one follow-up on the portfolio agreements, you mentioned Ireland, Australia, Denmark and Netherlands. So, as we model 2019 SYMKEVI sales, would it be reasonable to expect revenue from those four territories as well as Germany?

So, in countries in the EU where we have a regulatory approval for 12 plus where those portfolio agreements are in place, we will be able to get access relatively quickly. I would remind you that in large parts, SYMKEVI is indicated for the same population as ORKAMBI and in places like Ireland for instance. On the Netherlands, we have seen very impressive uptake of ORKAMBI and very high persistence rate. And so whilst patients and physicians will have a choice essentially they will be trading up, which they think is the best medicine.

That’s helpful. Thank you.

Thank you. Our next question comes from Alethia Young of Cantor Fitzgerald. Your line is now open.

Hi, Alethia, you are on mute?

Can you hear me?

We hear you now.

Yes. Okay, cool. Maybe that’s wrong with my headset. Sorry I apologize. I just wondered if you could talk a little bit about kind of your thoughts on M&A I mean you have a pipeline is coming together obviously internally, but I just wanted to talk a little bit about what you might think it’s supplemental and interesting around doing external M&A or anything like that? And then also is that kind of delayed until you kind of figure out the CFO position as well? Thanks.

Yes, Alethia, this is Jeff. I will take those. As you know, for the last couple of years, we’ve been talking about a consistent, what I call external innovation strategy, not just M&A with licensing collaboration etcetera. it’s really focused around three areas. The first is obviously yes, where anything that we feel would be complementary or additive to our current regimens would be of great interest to us. Honestly, we’re seeing less and less in that particular bucket simply because we’ve set such a high bar now with the triple combination data. The second area is what I call technology and tools had a very concerted effort to build a complete tool box of technologies that we think would allow us to address the kind of serious diseases and to some extent genetic diseases that we’re interested in and our pipeline. And you’ve seen us do a number of those deals, so CRISPR, Arbor, X-Chem, and Genomics Plc. Those are all deals and you should think of it’s acquiring different tools that will the let us optimally address the diseases that we’re interested in. You should expect to see us continue to do that in areas of interest, nucleic acid therapies, gene therapies etcetera. And then the third area would obviously be pipeline assets. And those pipeline assets would be consistent with our overall strategy of transformative medicines for serious diseases and specialty markets. And you should expect to see us do some of those as we find them in general, but the earlier stage development assets where we think we can add value through our clinical development regulatory and commercial groups. What you won’t see us doing is deals for on-market or late-stage products that are essentially led by revenue growth over the next 5 years to 7 years simply because we don’t need that revenue growth, CF is going to provide that. And so you can expect to see us continue to do deals around those three focus areas. I would say that we are obviously building substantial financial firepower to do more of those deals and we’ve ramped up our external innovation group to allow us to do that. And so I do think it’s fair for you to expect to see us complement our very rapidly advancing internal pipeline with some external innovation as well.

Thanks a lot. Very thorough.

Thank you. And our next question comes from Geoff Meacham of Barclays. Your line is now open.

Hey, guys. Thanks for the question. I know the plan is still obviously to select the NDA for the triple coming up in the first half. I just want to ask if your points of differentiation between the two or the metrics have changed at all. In other words, like is it still about FEV1 and maybe less about pulmonary exacerbations or the like? And then also when you look at the part of the package, is there anything that has yet to be done in terms of non-clinical or that could be perhaps or getting factor or something that could push you to the second half of the year versus the end of 2Q your guidance? And I have one follow-up.

Thanks, Geoff. This is Jeff. I’ll take the first part and Reshma maybe you can take the second part. With respect to how we’re going to compare the two assets, again, just I know you this, but just a quick review, we – not that the 445 drivers fully enrolled, we have a very good line of sight to the timing of when we expect to see the top-line data there, which is in the first quarter. And so we’re very confident that we’ll have that kind of data that we can compare to the data that we’ve already reported for 659. As I said before, the way we’re going to look at these two assets is the complete profile, if you will of both programs and that goes all the way back to preclinical work. It includes things like PK, PD, tolerability, drug-drug interactions, as well as of course the efficacy measurements, that you talked about with FEV1, but also things like sweat chloride. So, this will be a very complete review of both assets. We’re in a nice position of having a nice complete file on both assets once we get the 445 data and I think we’ll be able to then pick the best asset to move forward. And again, we’re very much on track to do that in the first quarter. We’re confident that we will be able to make that decision on schedule in the first quarter, which would allow that mid-year NDA filing. But I’ll let Reshma address the second part of the question with respect to the package and what’s there.

Sure. Thanks, Jeff. So, regardless of whether the selection is for VX-659 or for VX-445, we’re going to have all of the data that we need in Q1, you know that we already shared the data for VX-659 late last year, the exact same package, the same amount of the data and the same kind of data we’re going to get very shortly for 445. And with regard to packaging, we’re making sure that we have the CTD complete in the NDA file, that’s going to happen by mid of this year. That is something that we are very much on track for and I have high confidence that’s going to happen.

Okay. And then just a follow-up, I know this was asked about the reimbursement, oh you asked, I know in the past, you guys have had a pretty defined strategy of allowing kind of the patient community to sort of escalate and maybe to put some pressure on the payers and this obviously has been the case in the UK and in France. But I wanted to ask you for the triple, is there a different methodology or just something you can do differently maybe to help accelerate reimbursement looking OUS, maybe just do things a little bit differently that could help speed up a process?

Yes, Geoff, it’s Stuart here. I wouldn’t say that it’s our strategy to get patients to put pressure on people as you know, our development plans in cystic fibrosis, there’re no secret to anybody that the community is very well aware of the progress we’re making, very well aware of the clinical benefits, these products look like they are delivering and so I think quite rightly they are calling on their elected officials to get access to these medicines. I really refer back to what I said earlier, the key here from a kind of health technology assessment point of view is that the methodology needs to be appropriate for these types of medicines, which are going to be used very early in people’s lives, hoping to restore them to normal levels of chloride transport and deliver benefits over the very, very long-term. And frankly, the assessment methodologies are not really fit for purpose to assess those types of medicines. So, from a health technology assessment point of view, that is what we are continuing to work on and where we’ve done that which is in many, many countries around the world, we’ve been successful. And then the other thing that I think is an important component of this is, where we’ve been successful. I think a substantial portion of the time, it’s because senior government ministers have taken an interest in this issue being able to see our portfolio and how fast it’s developing and the kind of benefits it could bring to their populations. And so to me those are two of the most important success factors in the UK and everywhere else around the world.

Thank you. And our next question comes from Paul Matteis of Stifel. Your line is now open.

Great. Thanks so much for taking my question. Two-part question on VX-150. I guess first of all, can you guys talk about the logic of doing more stringent work here. Given that you have a few positive Phase 2, a low AE rate, and there’s a big unmet need for an opioid alternative, we were just wondering why – why not move faster into Phase 3? And then secondarily, I was wondering if all strategic options with VX-150 still on the table and have you confirmed that you’ve picked as far as yourself at least to a targeted subset or it’s an out-licensing still a possibility? Thanks so much.

Sure, thanks. This is Reshma. Let me take the first half of your question and then I’ll pass it on to Jeff for the second half of your question. So, with regard to VX-150 which is our NaV1.8 inhibitor that you pointed out we’ve had now three out three successful studies in osteoarthritis in small fiber neuropathy as well as in bunionectomy. The reason that we are doing dose-ranging is really two very simple points. One is regulatory. Regulators expect us to do dose-ranging and really what they’re looking for us to do is to find the lowest efficacious dose and so one is just a very practical point around the regulators. The second point is around just a drug development. What we did in order to get a proof of mechanism read-out is we chose a high dose. Now what we need to do is to figure out what is the exposure response relationship, of course, that has important implications for picking not only the lowest efficacious dose, but also what the dose will be which informs pill size and that informs COGS and other such things. So that’s really what we’re doing. I do want to let you know that the update on that one is that the Phase 2b is now fully enrolled. So, we’re going to be in a good spot to understand all of those pieces of information in the near future.

And maybe I’ll take the second part. The question is really a commercial strategy question, I think. As I said before, we don’t think of pain as a single commercial market. We think of it as multiple markets, as an example acute pain, which is essentially post-surgical, post procedural pain, mostly in hospitals, outpatient surgery centers or dentist office is in itself a multi-billion dollar opportunity, typically you’d like to have both NaV and an oral form of a new LNG like in that market. That’s very much a specialty market because we can address large parts of that market ourselves and it would be our plan assuming we have the data supports it to pursue development and commercialization of that market ourselves, small fiber neuropathy, similarly a market that’s typically in a set of pain specialists offices. It’s a market that can be addressed as a specialty market and it’s one that again with appropriate data, we feel that we could develop and commercialize ourselves. You know very, very different from the chronic inflammatory pain that’s OA, low back pain et cetera, that’s predominantly a primary care market. And then from our perspective, it’s not a market that we would want to build a commercial presence and develop and that’s one where you might see us go with the partner. We have had a fair amount of interest as you might imagine given due to, first, we won the class of analgesics from partners who have a lot of experience in these community pain markets. Does that answer your question about our commercial strategy?

Yes. It does. Thank you very much.

Sure.

Thank you. Our next question comes from Terence Flynn of Goldman Sachs. Your line is now open.

Hi. Thanks for taking the question. I was just wondering, if you can at all help us quantify the impact of improved persistence on SYMDEKO relative to ORKAMBI. And maybe how this compares to KALYDECO recognizing you have a lot more data on KALYDECO now, I think even now 5 years plus? Thank you.

Yes, Terence, without getting into the exact specifics and kind of the exact numbers because these things fluctuate over time and obviously SYMDEKO were 12 months into the launch, ORKAMBI is a lot longer, KALYDECO is more like 6 years. But certainly, the persistence we’ve seen on SYMDEKO is as we anticipated higher than we saw with ORKAMBI, it’s not quite at the level that we saw with KALYDECO, which were the highest personally I’ve ever seen for any mentioned in the many years I’ve been doing this, so it’s somewhere between ORKAMBI and KALYDECO, but SYMDEKO certainly is above ORKAMBI.

Okay. And then any more details you can give us on the patient mix for SYMDEKO and if you guys seen any warehousing in the U.S. ahead of the triple combo potential launch? Thanks.

So, in terms of the uptake, we’ve actually seen broader uptake for SYMDEKO across all of the patient groups that you would expect. It’s been taken up rapidly in naive patients, patients who’ve never been on ORKAMBI, those who were discontinued from ORKAMBI, and then we’ve also seen a fair number of patients switch from either ORKAMBI to KALYDECO. So, we’ve really seen uptake broadly across all of the eligible patient populations.

Okay. Thanks a lot.

Thank you. Our next question comes from Robyn Karnauskas of Citi. Your line is now open.

Hi. Thank you guys for taking my questions. So actually, so first of all, for switching to SYMDEKO, what are you learning about ORKAMBI patients or KALYDECO patients that are switching on the SYMDEKO given that there is longer part like the SYMDEKO and the triple going forward, are you seeing switching in mind with these patients, do you think it’ll be captive to point? Second question is just a follow-up and a [indiscernible] question. It seems like a change from JPMorgan that you might look externally for a pipeline asset, if you remember at JPMorgan, you discussed looking more for a platform to develop your – to get the science and help make [ph] drug. Are you just seeing something in the market, are things looking cheaper, what might have changed or how are you thinking about it differently? Thanks.

Hey, Robyn, it’s Stuart here. I’ll take the first question and then Jeff can take the pipeline next to your innovation question. So, in terms of what we’re seeing with patients who switch from KALYDECO to SYMDEKO or ORKAMBI to SYMDEKO, I mean, generally we’re seeing those patients have a great experience. We aren’t seeing many of those patients either discontinue or kind of go back to their original medication. As you know from the data or in the RF population, we saw [indiscernible] add substantial clinical benefit on top of either capital, and so that’s I think is what’s driving the majority of people who are making that transition. Obviously, with SYMDEKO and ORKAMBI, we don’t have as much in the way of direct comparative data, but I think it’s the overall benefit risk profile of SYMDEKO that I think people are finding attractive and that transition is going in line with our expectations. And then in terms of the external innovation, I’ll hand that back to Jeff.

Hey Robyn, it’s Jeff. Maybe just one other point on your question to Stuart about the switching, because obviously this is relevant as well to the triples, and just going to depend on the data and the label and lots of other things. But I do think the strategy here is to continue to provide better and better medicines for more and more patients, including the patients who are not on drugs. And so assuming that the data that we’re seeing now with 659, which is significantly better as you know than SYMDEKO even in performance valuation, we do expect over the long-term the vast majority of these patients will switch over to triple. So that’s just a sort of sideline for the future. With respect to the pipeline and the BD strategy, I apologize if I miscommunicated that to you JPMorgan obviously did our strategy is the same all along. So, the three buckets of CF as you point out technology and tools and certainly, we’ve done a lot of those deals and we’ll continue to do them. But we’ve always been interested in early stage pipeline assets that meet our strategy meaning they’re potentially transformative drugs for serious diseases. As you know, they’re not that easy to find. But we continue to look for them and certainly if we find them in diseases register then you should expect us to see to do in licensing or acquisition deals on those early stage assets.

Thank you.

Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. Your line is open.

Hi. Thanks very much for taking my questions and congrats on the quarter. I was wondering if you could give us a little bit more color on the contribution of uptake in 2 to 5-year-olds to ORKAMBI revenues maybe relative to background the background dynamic of adult switching to SYMDEKO. And then separately on the triple, as you get more data in hand, I am curious what type of translational or maybe educational work you’ll need to do to bridge the shorter term functional benefits from Phase 3 to the long term outcomes that you’ve seen with other treatments like KALYDECO that have been dosed over the course of years and whether you’ve had any preliminary pay or discussions or feedback on that front? Thanks.

So, Brian I will take the first question on ORKAMBI, so we have seen a strong uptake with ORKAMBI in the two to five-year old patient groups and as you might imagine that kind of helps to lead to a very strong quarter for ORKAMBI and if you like kind of compensate for the fact that there are a number of patients who are switching from ORKAMBI to SYMDEKO as you know because of these dynamics with patient populations and the same medicines being approved and in those same patient populations that’s why we’ve really gone to getting triple CF product guidance now because it’s hard to be specific about each and every one of these patient population and exactly how many people are going to be on each medicine and so that’s why we’ve gone to triple CF revenues now. And then in terms of the triple data all that I will hand it over to Reshma.

Sure. So with regard to triple combination, as you know the primary endpoint in both the 445 and 659 programs for the FX studies or ppFEV1 have four weeks and in the FMS study, it’s the interim analysis at 4 weeks ppFEV1. Now it’s very interesting in that is the reason we decided to go forward with a ppFEV1 in four weeks is because, as you can imagine, we have a treasure trove of data looking at ppFEV1 over time through our KALYDECO experience, ORKAMBI, and SYMDEKO, and what you see is that there is a very consistent relationship with what you see with CFTR modulators at week four and what you see later on for example at week 24 or week 52. And so I think that relationship is actually reasonably well understood amongst physicians as well as patients. The other interesting thing to note is of course in the SMS studies for both 659 and 445, we’re going to have the 24-week ppFEV1, so we can start to do some analysis of rate of decline and such. And we are also going to have pulmonary exacerbations, BMI, CFTR. So, it’s actually quite a bit of data that’s coming and I’ve been very impressed with how well the studies have been understood by the community, not just the physicians but the patients as well.

Thanks very much.

Thank you. Our next question comes from Matthew Harrison of Morgan Stanley. Your line is now open.

Great. Thanks very much. I guess Paul I was wondering if you could talk a little bit about the operating margin progression. You’ve obviously moved up 7 or 8 points this year. How should we think about that relative to the revenue growth you’re talking about in 2019 and beyond thanks very much?

Yes, I highlight. It’s Jeff actually. Maybe I will take a little more of a strategic question since we’ve given you the guidance for 2019. So, as we look forward and that as you’ve seen over the last couple of years there’s a pretty consistent trends here of growing revenues considerably faster than operating expenses, which obviously results in operating margin expansion and increases in operating income. And I think as Paul mentioned as we look forward to next year, we expect to see our current guidance of 15% top line revenue growth, but a 21% growth in operating margin reflecting exactly the same pattern going forward in 2019. Obviously, as we get to triples, that only accelerates because revenue grows even faster after the triple launches and operating expenses. We have maintained a pretty disciplined approach. So, I think if you think about this long term, without giving you long term guidance, you should think about continued operating margin expansion and operating income increases, which also results in the cash flows, that Paul mentioned, does that give you enough detail on sort of how we think that going forward.

Yes, that’s very helpful. And then if I can just ask one pop. I mean other people have asked about ex-U.S. reimbursement on the call. I was wondering if you could just specifically address some of the news around compulsory with licensing in some active countries and what you see as the path forward there the likelihood of anything happening there?

Yes, Matthew. It’s Stuart here. I mean the compulsory license issue is probably most recently been discussed in the UK yesterday. There was a debate on crown uses as they call it in the UK I think it’s fair to say that the government itself in that debate recognized that this is a very complicated issue. It’s not entirely a viable option for multiple reasons including that it’s inconsistent with their desire to foster a vibrant life sciences ecosystem. We certainly agree with their perspective on that. I would say, we’re not really focused or particularly concerned frankly about compulsory licensing what we’re focused on is finding a solution in the short term for patients that provides access to ORKAMBI as soon as we can and our pipeline of future medicines as soon as they’re approved.

Great. Thank you very much.

Thank you. Our next question comes from Cory Kasimov from JPMorgan. Your line is now open.

Hi, good afternoon, guys. Thanks for taking my question. I wanted to ask about AAT and wondering if you can talk about the potential cadence of initial clinical data and what you might expect to learn from healthy volunteers. And then I realize this is putting in the cart before the horse a little here, but assuming the early clinical stage work goes well what might a registrational pathway for this indication potentially look like I’m curious would you expect it to be biomarker outcome driven just trying to broadly understand what this program may encompass? Thanks.

Sure. This is Reshma. Let me take those parts of that question. With regard to the cadence of the trial, so let me quantify this fairly small molecule approach that we are taking here, that similar extending those powered by multiple ascending dose that’s going to be done in healthy volunteers and as soon as we get through that we’re going to be ready to go into patients. The good news on this program is that it’s going to be a reasonably efficient program I don’t know if it’s 30, 40 people but a reasonably efficient program for us to be able to see whether our molecules going to have the intended effect, which is elevation in AAT level and in activity. This is a fairly standard readout and so we expect to have that in hand in the near future as soon as we get through our healthy volunteer studies. With regard to the registration path that we were early in here that, what I can tell you is that the existing therapies, which you know are [indiscernible] therapy so it’s an infusion of the protein. Those were approved at about four of them available on the market and those were approved based on AAT levels. So that’s one data point that you have to start with. We have to go through our conversations with regulators to see what the Phase 3 registration enabling end points are going to be here. But I do think that’s an important data point to look at.

That’s helpful. Thank you.

Thank you. And our next question from Hartaj Singh of Oppenheimer and Company. Your line is now open.

Great. Thank you for my question. Just a question on the two triple X I know that in November you’d also indicated you had 12-week data and 26-week data that 659 had gone through. Can you just give us an update as to how you report that the safety data also for both the projects as the efficacy readouts are coming up? Thank you.

Sure. If I go back to our 659 release from late last year, I think that gives you a very good template for how you can expect to hear our share of the data for 445 which will be coming this quarter in terms of both safety and efficacy. So, on the efficacy side, you’re going to hear us tell you about the ppFEV1 at four weeks from both the FX and the FMX trial. And with regard to safety, now on this one, we’re going to give you the top line with regard to discontinuations overall tolerability. But we’re going to be very, very thoughtful about maintaining study integrity and we’re not going to go very far beyond that, just like you thought to do with 659.

Thank you.

Operator, we are now at the 1 hour mark. So, we will have time for one more question.

And our last question comes from Liisa Bayko of JMP Securities. Your line is now open.

Hi. Well a lot of my question’s been asked but I did want to ask about the triple and sort of if you could describe the patent life around the triple, that’d be helpful. Thank you.

Liisa, thank you so much for asking that. Since you get to that, so as you know, our plan is to co-formulate these into a single pill in which case the patent life around the medicine is actually determined by the longest patent life of the ingredients single ingredients. And in the case of the VX-659 and VX-445 which folks have pending pattern applications, the patent expiry if granted would be 2,037 in both the U.S. and Europe.

And any extension of that or that would be a query that’s it.

By 2030 is there, I’m going to be way too early to think about it. We’re obviously, we’re pleased with that pattern ways and we really can’t speculate on any extensions at this point.

Alright. Thanks very much. Congratulations on a good quarter.

Thanks, Lisa. Thank you for joining us tonight. The Investor Relations team is in the officer and they’re happy to do any further follow-up questions.

Thank you, ladies and gentleman. Thank you for participating in today’s conference. This conclude today’s program. You may all disconnect. Everyone, have a great day.