Q3 2019 Earnings Call

Good evening. This is Michael Partridge, Senior Vice President of Investor Relations.

Geoffrey Christopher Meacham: Good evening, this is Michael Partridge, Senior Vice President of Investor Relations. Tonight, we will review with you Vertex's business progress and provide our third quarter financial results.

Tonight, We will review with you Vertexs business progress and provide our third quarter financial results.

Unknown Executive: Making prepared remarks on the call tonight, we have Dr. Geoff Lydon, Chairman and CEO, Stuart Arbuckle, Chief Commercial Officer, Dr. Reshma Kewalramani, Chief Medical Officer, and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded, and a replay will be available 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 continuing development and 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. I will now turn the call over to Dr. Jeff Leiden.

Making prepared remarks on the call Tonight, we have Dr., Jeff Leiden, Chairman and CEO Stuart Arbuckle, Chief Commercial Officer, Dr. Rush, Mckay, well, Romani, Chief Medical Officer, and Charlie Wagner Chief Financial Officer.

We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded and a replay will be available on our web site.

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 vertexs marketed CF medicines, the continuing development and commercialization of our triple combination regimens for cystic.

Process Bridgetex is other programs and Vertexs future financial performance are based on managements current assumptions actual outcomes and events could differ materially.

Dr. Jeff Leiden: Thanks, Michael. Good evening, everyone.

I will now turn the call over to Dr., Jeff Leiden.

Thanks, Michael Good evening, everyone.

Dr. Jeff Leiden: 2019 has been a year of significant progress for Vertex across all parts of our business, as we continue to execute on our clear and differentiated strategy to create transformational medicines by investing in serial scientific innovation. Our significant growth in revenues from treating more people with CF globally has enabled continued investment in both internal and external innovation to create future medicines. And we are making rapid progress across our pipeline in our efforts to advance additional potentially transformative medicines, both in CF and multiple other serious diseases. Our strategy is working and has positioned the company for continued growth in 2020 and for years to come. I'm pleased to review with you some of our recent accounts. First, to CF.

29, P. it has been a year of significant progress for vertex across all parts of our business as we've continued to execute on are clear and differentiated strategy to create transformational medicines by investing in cereal scientific innovation.

Our significant growth in revenues from treating more people with CF globally has enabled continued investment in both internal and external innovation to create future medicines, and we're making rapid progress across our pipeline and our efforts to advance additional potentially transformative medicines, both in CF and multiple.

Other serious diseases.

Our strategy is working and its position the company for continued growth in 2020 and for years to come I'm pleased to review with you some of our recent accomplishments.

First the CF.

Dr. Jeff Leiden: I'm proud to say that last week's FDA approval for Trikafta marks the most significant step to date in our more than 20-year journey toward our future goal of curing CF for every person with this disease. I joined Vertex as CEO eight years ago, right before we received our first approval for Kalydeco to treat the cause of CF in a small group of patients in the U.S. Today, approximately 45,000 patients worldwide are eligible for one of our four CF medicines, and we're treating thousands of patients in more than 30 countries around the world. I would like to again thank the patients, families, caregivers, physicians, and advocates, as well as the CF Foundation, who have been on this journey with us over the past two decades.

I'm proud to say that last week's FTC approval for try CAFTA marks the most significant step to date in our more than 20 year journey toward our future goal of curing CF for every person with this disease.

I joined vertex the CEO eight years ago right before we received our first approval for Kalydeco to treat the cause of CF for a small group of patients in the U.S.

Today, approximately 45000 patients worldwide are eligible for one of our for CF medicines, and we're treating thousands of patients in more than 30 countries around the world.

I would like to again, thank the patients families caregivers physicians and advocates as well as the CF Foundation who've been on this journey with us over the past two decades.

Dr. Jeff Leiden: The approval of Trikafta would not have been possible without the unwavering support of the entire CF community. I would also like to highlight the significant progress we've made throughout 2019 in securing reimbursement for our medicines outside the U.S. Most notably, we recently announced new reimbursement agreements for Acambi and Simkevi in England, Spain, Australia, and Scotland. I'm pleased that eligible patients in these countries now have a medicine to treat the underlying cause of their CF for the first time, and that we are able to work collaboratively with governments to reach agreements that appropriately value the scientific innovation and clinical benefit of our medicine. Now to our pipeline.

The approval of try CAFTA would not have impossible without the unwavering support of the entire CF community.

I would also like to highlight the significant progress we've made throughout 2019 in securing reimbursement for our medicines outside the U.S.

Most notably we recently announced new reimbursement agreements were a can be and some kabi in England, Spain, Australia in Scotland.

I'm pleased that eligible patients in these countries now have a medicine to treat the underlying cause of their CF for the first time and that we were able to work collaboratively with governments to reach agreements that appropriately valued the scientific innovation and clinical benefit of our medicines.

Now to our pipeline.

Dr. Jeff Leiden: Today, we have multiple different potentially transformative medicines in clinical development spanning five specialty diseases, and we're entering a period of significant clinical development progression and data generation for these programs. In fact, we expect multiple proof-of-concept data readouts and the initiation of key proof-of-concept studies through 2020 that will represent important risk-lowering events for our pipeline. Our pipeline investments have, for several years, followed a disciplined strategy focused on causal biology, building highly predictive preclinical models and developing biomarkers early in development to lower risk and increase our probability of success in the clinic, and we only work on transformative medicines for serious diseases that create and sustain significant value for patients, society, and our shareholders.

Today, we have multiple different potentially transformative medicines and clinical development spending five specialty diseases, and we're entering a period of significant clinical development progression data generation for these programs.

In fact, we expect multiple proof of concept data readouts in the initiation of key proof of concept studies through 2020 that will represent important risk lowering events for our pipeline.

Our pipeline investments have for several years, followed a disciplined strategy focused on causal biology.

Building highly predictive preclinical models and developing biomarkers early in development to lower risk and increase our probability of success in the clinic.

And we only work on transformative medicines for serious diseases that create and sustain significant value for patients society and our shareholders.

Dr. Jeff Leiden: Our external investments are aligned with this strategy and encompass multiple therapeutic modalities. We have increased our external investment in line with our growing cash flow by acquiring new development programs and building a toolkit of new technologies that will enable us to develop breakthrough medicines in diseases such as type 1 diabetes, Duchenne muscular dystrophy, hemoglobinopathies, and others. Most recently, we acquired Thema Therapeutics with the goal of developing a cellular therapy that both alone and in combination with an implantable device has the potential to cure type 1 diabetes. This acquisition is a perfect example of our efforts to bring in promising development programs that complement our internal R&D efforts, are aligned with our strategy, and provide significant opportunities for further growth beyond CF.

Our external investments are aligned with the strategy and encompass multiple therapeutic modalities, we've increased our external investment in line with our growing cash flow by acquiring new development programs and building a tool kit of new technologies that will enable us to develop breakthrough medicines diseases, such as type one diabetes duchenne muscular dystrophy.

Hemoglobinopathies and others.

Most recently, we acquired cemetery computers with the goal of developing a cellular therapy that both alone and in combination with an implantable device has the potential to cure type one diabetes.

This acquisition is a perfect example of our efforts to bring in promising development programs to complement our internal R&D efforts.

Lined with our strategy and provide significant opportunities for further growth beyond CF.

The execution of our corporate and research strategies has produced a highly differentiated profile for both near term and long term growth.

Dr. Jeff Leiden: The execution of our corporate and research strategies has produced a highly differentiated profile for both near-term and long-term growth. As we continue to expand access to our medicines worldwide and gain approvals for new medicines, we are well positioned for further revenue and earnings growth and for continued reinvestment in innovation that creates future medicines. I look forward to updating you on our progress over the coming months and will now turn the call over to Stuart to talk in more detail about our commercial performance and the launch of Trikafta.

As we continue to expand access to our medicines worldwide gain approvals for new medicines, we are well positioned for further revenue and earnings growth and for continued reinvestment in innovation the create future medicines I look forward to updating you on our progress over the coming months and we'll now turn the call over to Stuart to talk in more detail about our commercial performance.

And the launch of try CAFTA.

Stuart A. Arbuckle: Thanks, Geoff. Tonight, I'll briefly review our commercial performance for the third quarter and discuss our expectations for the ongoing launch of Trikafta in the U.S. Our third quarter total product revenues were $950 million, a 21% increase compared to the third quarter of 2018. This increase is as a result of treating more patients globally with our medicines. Uptake across multiple products and in multiple populations drove revenue growth over the past year, most notably from Symdeco and Symkevi in patients ages 12 and older. We also saw revenue growth as a result of expansion into younger patients, including children in the U.S. ages 2 to 5 years for Orkambi and ages 6 to 11 years for Symdeco. Outside the US, we continue to make progress in achieving reimbursement for our CF medicines, Orkambi and Simkevi, as evidenced by our recent announcements regarding reimbursement in England, Spain, Scotland, and Australia. Together, our progress in these countries underscores the positive outcomes that can be achieved when we and governments work collaboratively and flexibly toward providing access for patients.

Thanks, Jeff.

Tonight I'll briefly review, our commercial performance for the third quarter and discuss our expectations for the ongoing launch of try catheter in the U.S.

Our third quarter total product revenues were $950 million.

21% increase compared to the third quarter of 2018.

This increase is as a result of treating more patients globally with our medicines.

Uptake across multiple products and in multiple populations drove revenue growth over the past year.

Most notably from seemed to co and some Kevin in patients ages 12 and older.

We also sold revenue growth as a result of expansion into younger patients, including children in the U.S. ages two to five years for ORKAMBI and ages six to 11 years syndicate.

Outside the U.S., we continue to make progress in achieving reimbursement for our CF medicines, ORKAMBI and some Kevin as evidenced by our recent announcements regarding reimbursement in England, Spain, Scotland and Australia.

Together our progress in these countries underscores the positive outcomes that can be achieved when we and governments work collaboratively and flexibly toward providing access for patients.

Stuart A. Arbuckle: Now to the approval and launch of Trikafta in the U.S. Trikafta is Vertex's fourth medicine to treat the underlying cause of CF and was approved by the FDA last week to treat people with CF ages 12 years and older who have at least one F508 del mutation. The speed of FDA approval is a reflection of not only the strength of the TRIKAFTA data but also of the community's shared urgency to provide patients with a medicine that treats the underlying cause of their disease. And I am pleased to report that the first patients have already been prescribed TRIKAFTA by their physicians, underscoring the strong interest in the medicine. The label for Trikafta is broad.

Now to the approval and launch of try CAFTA in the U.S.

Try CAFTA is vertex is fourth medicine to treat the underlying cause of CS.

And was approved by the FDA last week to treat people with CF Ages 12 years, an older with at least won five await del mutation.

The speed of the FDA approval is a reflection of not only the strength of the try CAFTA data, but also of the community shed urgency to provide patients with a mentioned that treats the underlying cause of their disease and I'm pleased to report the first patients have already been prescribe try CAFTA by their physicians underscoring the strong interest in the Mets.

The label for try CAFTA is broad.

Stuart A. Arbuckle: Any patient in the U.S. aged 12 years or older with at least one F508 del mutation is eligible. We estimate that there are approximately 18,000 patients in the U.S. who fit these criteria, representing by far the largest population of CF patients eligible for one of our CF medicines at the time of launch. Of the 18,000 patients eligible for TRIKAFTA, approximately 6,000 are those with one F508 del mutation and one minimal function mutation who until now have not had treatment for the underlying cause of their CF. The remaining approximately 12,000 patients are those who are already eligible for one of our CF meds, and most of these patients are currently being treated with Kalydeco or Camby, or Symdeca. Revenue growth in 2020 will be driven primarily by the treatment of new minimal function patients.

Any patient in the U.S. age 12 years are older with at least one F. Five await del mutation is eligible.

We estimate that there were approximately 18000 patients in the U.S., who fit these criteria representing by far the largest population of CF patients eligible for one of our CF medicines at the time of the launch.

Well the 18000 patients eligible for try CAFTA approximately 6000, those with won five await del mutation and won minimal function mutation.

Who until now have not had treatment for the underlying cause of SCS.

The remaining approximately 12000 patients are those who were already eligible for one of us CF medicines and most of these patients are currently being treated with kalydeco or ORKAMBI or syndicate.

Revenue growth in 2020 will be driven primarily by treatment of new minimal function patients.

Stuart A. Arbuckle: And over time, we expect that the vast majority of the 6,000 new minimal function patients will be treated with Trikafta. We also expect that a significant proportion of patients currently on Kalydeco or Camby or Symdeco will switch to Trikafta over time. The large number of eligible patients, coupled with the capacity constraints of CF centers to schedule and actually initiate such a large volume of patients, are important factors in why it may take longer for the Trikafta launch to reach its peak level of uptake compared to prior launches. Reimbursement is an additional factor in the launch of Trikafta. We expect to obtain broad reimbursement from both commercial and government payers in the U.S., similar to our experience with prior CF medicines.

And over time, we expect the vast majority of the 6000, new minimal function patients will be treated with try CAFTA.

We also expect that a significant proportion of patients currently on kalydeco or ORKAMBI or seemed to go we'll switch to try CAFTA overtime.

The large number of eligible patients coupled with the capacity constraints of CF centers to shed jewel and actually initiate such a large volume of patients.

Important factors in why it may take longer but the try CAFTA launch to reach its peak level of uptake compared to prior launches.

Reimbursement is an additional factor in the launch of try CAFTA.

We expect to obtain broader reimbursement from both commercial and government payers in the U.S. similar to our experience with prior CF medicines.

Stuart A. Arbuckle: We've already begun discussions with payers following the approval, and the initial feedback has been positive based on the strength of the clinical data and payers' understanding of the disease-modifying benefits that our medicines provide. These dynamics are reflected in our updated total 2019 CF Revenue Guidance of $3.7 to $3.75 billion that we provided at the time of the TRICAFTA approval last week. We will also take these factors, as well as early uptake trends, into account as we set guidance for 2020 early next year. In summary, I am pleased that we are bringing our medicines to many more patients around the globe and on the trajectory of our continued revenue growth. With that, I will now turn the call over to Reshma to review recent pipeline progress.

We've already begun discussions with payers following the approval and the initial feedback has been positive based on the strength of the clinical data.

Pay his understanding of the disease modifying benefits that are medicines provide.

These dynamics are reflected in our updated total 2019, CF revenue guidance of $3.7 billion to $3.75 billion that we provided at the time of the trike after approval last week.

We will also take these factors as well as early uptake trends into account as we set guidance for 2020 early next year.

In summary, I'm pleased that we are bringing on medicines to many more patients around the globe and with the trajectory of our continued revenue growth.

With that I'll now turn the call EBITDA Rushmore to review recent pipeline progress.

Reshma Kewalramani: Thanks, Stuart. I would first like to echo Geoff's comments about the significance of the Trikafta approval, both for Vertex and for the CF community. It's truly amazing to think that it was in early 2016 that our scientists first synthesized AlexaKafta, the next-generation corrector that became a key part of Trikafta, and in a little under four years, Vertex was able to bring that molecule from the lab through development and now to patients in the US. It's a remarkable story of drug development, and I'd like to thank the entire As we celebrate this milestone, we are also working diligently to bring Trikafta to more patients globally and to gain approvals for younger patients. We are on track to seek additional regulatory approvals for Trikafta outside the U.S., first in Europe, then in additional countries globally.

Thanks, Stuart I would first like to Echo Jeffs comments about the significance of the try captor approval, both for vertex and for the CF community.

It's truly amazing to think that it was in early 2016 that our scientists first synthesised elects to capture the next generation corrector that became a key part of try CAFTA.

And in a little under four years vertex was able to bring that molecule from the lab through development and now to patients in the U.S.. It's a remarkable story of drug development and I'd like to thank the entire see if community for their support in getting us to this milestone.

As we celebrate this milestone we're also working diligently to bring track after two more patients globally and to gain approvals for younger patients. We're on track to seek additional regulatory approvals for track CAFTA outside the U.S. first in Europe than in additional countries globally.

Reshma Kewalramani: And we are also now enrolling a phase 3 study of Trikafta in children ages 6 to 11 years. Outside of CF, we are entering a period of significant data generation and clinical development progress. We expect multiple important clinical data readouts from our pipeline beginning later this year and the progression of multiple molecules into Phase I and Phase II studies throughout 2020. For sickle cell disease and beta thalassemia, we expect to provide the first clinical data from the Phase I-II studies of the novel gene editing therapy CTX001 later this year with our partner CRISPR Therapeutics. The data we expect to disclose will include measurements of safety and efficacy for patients with beta thalassemia and sickle cell disease treated with CTX001. In our AAT program, we have now finalized the design of a Phase II proof-of-concept study for our first oral small-molecule corrector, VX814, and expect to begin the study this quarter. The study is expected to enroll approximately 50 patients with AAT deficiency who have two Z mutations and will evaluate multiple doses of VX814 compared to placebo for 28 days. The primary endpoint will be the change in the level of functional AAT protein in the blood, as well as safety and tolerability. We expect to obtain data from the study in 2020.

And we are also now enrolling a phase three study of try catheter in children ages six to 11 years.

Outside of Seattle, we are entering a period of significant data generation and clinical development progress. We expect multiple important clinical data readouts from our pipeline. Beginning later this year and the progression of multiple molecules into phase one and phase two studies throughout 2020.

In sickle cell disease, and beta thalassemia, we expect to provide the first clinical data from the phase one two studies of the novel Gene editing therapy. CTX 001 later this year with our partner CRISPR Therapeutics.

The data we expect to disclose will include measurements of safety and efficacy for patients with beta thalassemia and sickle cell disease treated with CTX 001.

In our ATM program, we have now finalized the design of a phase two proof of concept study for our first oral small molecule corrector VX eight one for and expect to begin to study this quarter.

This study is expected to enroll approximately 50 patients with 80 deficiency, who have to Z mutations and we'll evaluate multiple doses of VX, one for compared to placebo for 28 days.

The primary endpoints will be the change in level, a functional 80 protein in the blood as well as safety and Tolerability.

We expect to obtain data from this study in 2020.

Reshma Kewalramani: In addition to VX814, we're also developing a second AAT corrector, VX864, which is currently in phase one development. For pain, we're advancing multiple selective NAV1.8 inhibitors through late-stage research and early clinical development, including our ongoing Phase I study of VX961. And in FSGS, we are on track to complete our Phase 1 study of VX147 in healthy volunteers later this year. VX147 is our first oral small molecule inhibitor of ApoL1 function, and if we are successful in Phase 1, our plan is to initiate a Phase 2 proof of concept study in 2020, where we would evaluate the ability of VX147 to reduce protein levels in the urine. This would represent an important biological proof of concept for this program, and similar to other pipeline programs, we are advancing multiple additional molecules for ApoL1-mediated kidney diseases in late-stage research. With the launch of Trikafta and the advancement of our pipeline of multiple other potentially transformative medicines across five serious diseases, 2020 is positioned to be a year of significant growth and pipeline progression for Vertex. I'll now turn the call over to Charlie.

In addition to VX one for we're also developing is second to 80 corrector VX Eightsix for which is currently in phase one development.

In pain, we're advancing multiple selective NAF 1.8 inhibitors through late stage research and early clinical development, including our ongoing phase one study VX 961.

And NFS, yes, we are on track to complete our phase one study of VX one for seven in healthy volunteers later this year.

Next one for seven is our first oral small molecule inhibitor of April one function and if we're successful in phase one our plans to initiate a phase two proof of concept study in 2020, where we would evaluate the ability of VX one for seven to reduce protein levels in the hearing.

This would represent an important biological proof of concept for this program.

And similar to other pipeline programs, we are advancing multiple additional molecules for April one mediated kidney diseases in late stage, we search.

With the launch of try CAFTA and the advancement of our pipeline of multiple other potentially transformative medicines across five serious diseases 20, twenties position to be a year of significant growth and pipeline progression for vertex.

I'll now turn the call over to Charlie.

Charles F. Wagner: Thanks, Reshma. In addition to Stuart's comments on the performance of our CF products, tonight, I'll review our third quarter financial results, our 2019 financial guidance, and make a few comments on our financial trajectory for 2020. All of the results and guidance I will discuss tonight are non-GAAP. As Stuart mentioned, we saw continued double-digit growth in total product revenues in the third quarter of 2019 compared to 2018, based largely on the uptake of Symdeco and Symkevi. Our third quarter 2019 combined R&D and SG&A expenses were $416 million, compared to $379 million for the third quarter of 2018. The significant growth in revenues and disciplined spending in the third quarter resulted in operating income of $403 million, a 37% increase compared to the third quarter of 2018. Net income for the third quarter of 2019 was $322 million, compared to $282 million in the third quarter of 2018.

Thanks, Rob in addition to Stuart's comments on the performance of our CF products Tonight, I'll review, our third quarter financial results, our 2019 financial guidance and make a few comments on our financial trajectory for 2020.

All of the results and guidance I will discuss Tonight, our non-GAAP .

As Stuart mentioned, we saw continued double digit growth in total product revenues in the third quarter of 2019 compared to 2018 based largely on the uptake of seemed to go and some Kevin.

Our third quarter 2019, combined R&D and SGN, a expenses were 416 million compared to 379 million for the third quarter of 2018.

The significant growth in revenues and disciplined spending in the third quarter resulted in operating income of 403 million, a 37% increase compared to the third quarter of 2018.

Net income for the third quarter of 2019 was 322 million compared to 282 million in the third quarter of 2018.

Charles F. Wagner: Our year-to-date financial results show similar trends of strong revenue growth and disciplined spending, resulting in exceptional operating income growth. Our total CF revenues through the third quarter of 2019 were $2.75 billion, a 27% increase over the same period in 2018. Our year-to-date combined R&D and SG&A expenses were $1.2 billion, compared to $1.13 billion for 2018, resulting in year-to-date operating income of $1.19 billion for 2019 compared to $763 million for 2018. To date, in 2019, we have invested approximately $1.5 billion in cash in external innovation through new acquisitions and collaboration. We ended the quarter with approximately $4 billion in cash in marketable securities compared to $3.2 billion at the end of 2018. I would note, however, that we completed our $950 million acquisition of Summit Therapeutics early in the fourth quarter, so that outflow was not yet reflected in our third quarter cash balance.

Our year to date financial results show similar trends of strong revenue growth and disciplined spending, resulting an exceptional operating income growth.

Our total staff revenues through the third quarter of 2019 were 2.75 billion, a 27% increase over the same period in 2018.

Our year to date combined R&D and SGN expenses were 1.2 billion.

Compared to 1.13 billion for 2018, resulting in year to date operating income of 1.19 billion for 2019 compared to 763 million for 2018.

As our profitability and cash flow increase as result of treating more CF patients globally, we have a clear strategy an intention to reinvest in both internal and external innovation to create future medicines to.

To date in 2019, we have invested approximately 1.5 billion in cash in external innovation through new acquisitions and collaborations.

We ended the quarter with approximately 4 billion in cash and marketable securities compared to 3.2 billion at the end of 2018 I would note. However that we completed our 950 million dollar acquisition of summit Therapeutics early in the fourth quarter.

So that outflow was not yet reflected in our third quarter cash balance.

Charles F. Wagner: As we look ahead to Q4 and 2020 and beyond, we expect continued increases in cash flow to provide more flexibility for additional deals to fuel our long-term growth. Now to 2019 guidance and high-level thoughts on our financial trajectory for 2020. As you know, we revised upward our guidance of total CF revenues with the approval of TRIKAPTA last week, and we are tonight reiterating our 2019 guidance for total CF product revenues, combined R&D and SG&A expenses, and our anticipated effective tax rate. The midpoint of our 2019 revenue guidance reflects strong 23% growth over 2018, and we are well positioned to continue our trajectory of significant revenue growth in 2020, driven primarily by The exact rate of revenue growth will depend in large part on the TRIKAFTA launch dynamics that Stuart reviewed earlier, specifically the capacity of CF centers to schedule and initiate the large volume of new and existing patients likely to seek treatment with TRIKAFTA, with significant revenue growth expected in 2020.

As we look ahead to Q4 and 2020 and beyond we expect continued increases in cash flow to provide more flexibility for additional deals to fuel our long term growth.

Now to 2019 guidance and high level thoughts on our financial trajectory for 2020.

As you know, we revised upward our guidance of total CF revenues with the approval of try CAFTA last week.

And we are Tonight, reiterating our 2019 guidance for total CF product revenues combined R&D NSG in a expenses and our anticipated effective tax rate.

The midpoint of our 2019 revenue guidance reflects strong 23% growth over 2018, and we are well positioned to continue our trajectory of significant revenue growth in 2020, driven primarily by the launch of try CAFTA in the U.S.

The exact rate of revenue growth will depend in large part on the try CAFTA lunch dynamics that Stuart reviewed earlier, specifically the capacity of CF centers to schedule and initiate the large volume of new and existing patients likely to seek treatment with try CAFTA.

With significant revenue growth expected in 2020.

We will also increase our investments in innovation, particularly following our recent acquisitions of Exone X and Semih.

While vertex operating expenses of typically grown in the range of 10% to 14% per year over the last few years. Our current expectation is that the rate of growth will be somewhat higher in 2020, as we invest in research and preclinical manufacturing for selling genetic therapies in support of our programs in type one diabetes DMD and other diseases.

Charles F. Wagner: We will also increase our investments in innovation, particularly following our recent acquisitions of Exonix and Thema. While Vertex's operating expenses have typically grown in the range of 10 to 14% per year over the last few years, our current expectation is that the rate of growth will be somewhat higher in 2020 as we invest in research and preclinical manufacturing for cell and genetic therapies in support of our programs in type 1 diabetes, DMD, and other diseases. Importantly, we expect our revenue growth to significantly outpace any increases in operating expenses, which will drive continued increases in operating income and expansion of operating margins. Currently, we plan to issue revenue and other financial guidance for 2020 at our Q4 earnings call once we've seen a few months of the Trikafta launch. I'm pleased with the continued performance of our business and look forward to updating you over the coming months. With that, I will hand the call back to Geoff.

Importantly, we expect our revenue growth to significantly outpace any increases in operating expenses, which will drive continued increases in operating income and expansion of operating margins.

Currently we plan to issue revenue and other financial guidance for 2020 at our Q4 earnings call. Once we've seen a few months of the try cap the launch.

I'm pleased with the continued performance of our business and look forward to updating you over coming months with that ill hand, the call back to Jeff.

Thanks, Charlie as we near the end of 2019 vertex is on track to meet or exceed the key goals. We outlined for you at the start of the year.

An important and often overlooked part of our success is the strength of the team we have in place to execute on our strategy and drive the success of the business.

With the launch of try CAFTA, increasing revenues from treating more people with CF globally. The pipeline that is expanding and progressing rapidly and a strong and diverse team committed to our strategy of cereal innovation, we have never been a stronger position than we are today with that I will open the line to questions.

Dr. Jeff Leiden: Thanks, Charlie. As we near the end of 2019, Vertex is on track to meet or exceed each of the key goals we outlined for you at the start of the year. An important and often overlooked part of our success is the strength of the team we have in place to execute on our strategy and drive the success of the business. With the launch of Trikafta, increasing revenues from treating more people with CF globally, a pipeline that is expanding and progressing rapidly, and a strong and diverse team committed to our strategy of serial innovation, we have never been in a stronger position than we are today. With that, I will open the line to questions.

As a reminder to ask the question the press Star one on your telephone withdraw your question press the pound key.

Please standby, while the compiled the county roster.

And our first question comes from.

Mr. Goldman Sachs.

Open.

Maybe just starting with the question on the reimbursement decisions that have played out recently in England in Spain in Australia in Scotland, how should we view the uptake trajectory in these regions in any implications for the fourth quarter.

Unknown Executive: As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

Yes, thanks for the questions as Stuart.

Unknown Executive: Please stand by while we compile the Q&A roster. And our first question comes from Salveen Richter of Goldman Sachs. Your line is now open. Thanks. Perhaps just starting with a question on the reimbursement decisions that have played out recently in England and Spain and Australia and Scotland. How should we view the uptake trajectory in these regions and any implications for the fourth quarter?

So obviously, we're thrilled has been a very productive quarter in terms of new reimbursement agreements, which is.

Great as we complete the journey from discovering these medicines to getting access for patients.

In terms of the uptake overall I would say really the consideration job the same in each of the markets. The way I would think about it is your firstly the various administrations and placed the process.

Stuart A. Arbuckle: Q&A So obviously, we're thrilled it's been a very productive quarter in terms of new reimbursement agreements, which is great as we complete the journey from discovering these medicines to getting access for patients. In terms of the uptake overall, I would say really the considerations are the same in each of the markets, and the way I would think about it is firstly, the various administrations have to put in place the process to allow physicians to prescribe these medicines. As an example, in England, they quoted that they were hoping to get that solved within 30 days. So obviously, there's a bit of a lag before we can even start treating patients. And then after that, you know, really, what I would be thinking about. The number of patients that we have there in each of those markets. We expect in those markets, much like the other markets around the world, that we will, over time, initiate the vast majority of those patients on one of the CFTR modulators that's been reimbursed.

To allow physicians to prescribe these medicines and as an example in England.

They quoted that they were hoping to get that sold within 30 days. So obviously, that's a bit of that lag before we can even staff initiating patients.

And then after that I really I would be thinking about.

Number of patients that we have there.

In each of those markets, we expect in those markets much like the other markets around the world that we will over time initiate the vast majority of those patients on worn off the CSC all modulators that spin reimbursed.

Yes across the world in general across products across geographies, we tend to see initiation rains in the 80% to 90% range.

As you know not everybody. Unfortunately can stay on the medicines, so we see persistence rates across products across markets somewhere in the 80% to 90% range and so.

When we do eventually reach steady state, it's a function of those two things that we need to factor in a compliance rate compliance rates. All medicines are as good as I've ever seen in my time in me in the industry there across products tend to be any 80% to 85% range. So those are the kinds of factors I would be taking into.

Stuart A. Arbuckle: You know, across the world, in general, across products, across geographies, we tend to see initiation rates in the 80 to 90% range. As you know, not everybody can stay on the medicine, so we see persistence rates across products, across markets, somewhere in the 80 to 90% range. And so when we do eventually reach steady state, it's a function of those two things. Then we need to factor in a compliance rate. The compliance rates on our medicines are as good as I've ever seen in my time in the industry, across products tend to be in the 80 to 85% range. So those are the kinds of factors I would be taking into account. And that tells you a little bit about where we're likely to get to at steady state. Really, then, the question is, you know, how long is it going to take us to get to kind of peak levels of uptake, and that really is governed by kind of a couple of things.

Account. So that tells you a little bit about where we're likely to get to at steady state I'm really that my question is how long is it going to take us to get Cana peak levels of uptake and that really is.

Given by kind of a couple of things one is the size of the eligible patient population. If you take somewhere like England. It's 5000 patients. That's a very large number all of those patients treated in the faulty CF centers in England, and so just like here in the U.S. There is a capacity constraint, but the sensors have to actually being able to see all.

Of those eligible patients and that's probably the biggest can have rate limit. So we certainly expect it gets to the vast majority those patients, it's just likely to ramp up over time.

Stuart A. Arbuckle: One is the size of the eligible patient population. 5,000 patients. That's a very large number, and all of those patients are treated in the 40 CF centers in England. And so just like here in the US, there is a capacity constraint that the centers have to actually see all of those eligible patients. And that's probably the biggest kind of rate limiter. So we certainly expect to reach the vast majority of those patients. It's just likely to ramp up over time. In terms of 19, we haven't included any adjustment in our 19 guidance just because those reimbursement agreements have come so late in the year. And obviously, we need to work our way through the administrative things I've just told you about before we can actually start initiating patients.

In terms of 19, we haven't included any adjustment xenon 19 guidance, just because those reimbursement agreements come so late in the yet and obviously, we need to work our way through the administrative things I've. Just told you about before we can actually saw initiating patients.

Great. Thanks, and then just a second question about the ATM program could you just comment on how many dose cohorts, you're looking at and what that does bizarre and could this transition into a registrational trial.

I mean its ratio.

So as I said in my prepared remarks, I think that you're going to see this phase two dose ranging study for VX eight one or look and feel very much like Rcs studies, it's going to be about 50 people or so a few dose cohort.

Unknown Executive: Great, thanks. And then just a second question about the AAT program. Could you just comment on how many dose cohorts you're looking at and what the doses are? And could this transition into a registrational trial?

Hey, Gary.

Reasonable timeframe I'll stay away from out of the specifics around the doses and such.

And I do think that this is going to be important in getting to our phase three study because this is indeed the study that's going to help us select the right. Joe So in that respect I think it's going to be very important.

Yes.

Thank you next question comes from Michael <unk> of Jefferies. Your line open.

Reshma Kewalramani: Hi Salveen. It's Reshma.

Reshma Kewalramani: So, as I said in my prepared remarks, I think that you're going to see this Phase 2 dose-ranging study for VX814 look and feel very much like our CF studies. It's going to be about 50 people or so, a few dose cohorts, and a very reasonable time frame. I'll stay away from the specifics around the doses and such, but I do think that this is going to be important in getting to our Phase 3 study because this is indeed the study that's going to help us select the right dose. So, in that respect, I think it's going to be very important.

Hi, guys. Thanks, two questions. Congrats on all the progress and try CAFTA approval, maybe you could just frame some at the expectations around the uptake try CAFTA early on and whether you would expect centers to prioritize all the HETMIN patients first you would.

That would be logical so even though they're swapping from others how much of a priority is that for the Het Mins first and then the other question relates to a follow up on a key maybe rational I think we all listen Qt eight hour workshop, but they seem to be quite interested Austrian functional data show how confident are you.

Unknown Executive: Thank you. And our next question comes from Michael Yee of Geoffrey. Join us now, open.

With that if we get positive data on 80 that a primary endpoint of just a t. would be sufficient for perclot. Thanks, so much.

Unknown Executive: Hi guys, thanks. I have two questions.

Stuart A. Arbuckle: Congratulations on all the progress and the Trikafta approval. Maybe you could just frame some of the expectations around the uptake of Trikafta early on and whether you would expect centers to prioritize all the Hetman patients first. You would think that would be logical.

Hey, Mike It's Joe ill take that try asked a question and then.

I will talk to 80, so in terms of truck. After obviously, we're thrilled to get the approval. So quickly as you know the label is.

Broad anybody with won five away Dell mutation, that's approximately 18000 patients here in the U.S.

Stuart A. Arbuckle: So even though they're swapping from others, how much of a priority is that for the Hetmans first? And then the other question relates to a follow-up on AAT. Maybe Reshma, I think we all listened to the eight-hour workshop, but they seem to be quite interested in functional data too. So how confident are you that if we get positive data on AAT, that a primary endpoint of just AAT would be sufficient for approval? Thanks so much.

All of those 18000 about 6000.

Patients you have a minimal function mutation on the other o'neil.

And as you all know those are the patients who don't currently have a medicine to treat the underlying causes that disease today.

In terms of uptake again this is going to be governed by a couple of things. One is the absolute capacity as CF centers is by far and away the largest number of eligible patients we've ever had.

Stuart A. Arbuckle: Hey Mike, it's Stuart here. I'll take the Trikafta question, and then Reshma will talk to AAT. So in terms of Trikafta, obviously, we were thrilled to get the approval so quickly. As you know, the label is broad. Anybody with one F508 del mutation, that's approximately 18,000 patients here in the US. Of those 18,000, about 6,000 are patients who have a minimal function mutation on the other allele, and as you well know, those are the patients who don't currently have a medicine to treat the underlying cause of their disease today. In terms of uptake, again, this is going to be governed by a couple of things. One is the absolute capacity at CF centers. This is by far and away the largest number of eligible patients we've ever had for any new product launch. For instance, more than twice as many as we had when we introduced Orkambi back in July 2015.

For any new product launch.

For instance, more than twice as big as we had when we introduced ORKAMBI back back in July 2015.

So clearly the capacity of sensors is going to be a challenge.

Prioritizing patients might we could just about everything from every different center I think if you don't want center, you'll get wall response, you talked to another you'll get another some have said that they will prioritize het mins. Some have said that they will treat that most severely impacted patients irrespective of what that.

Mutation as others have said they will get to treat patients as they are coming in so I look to tell you. There's one also to help treat patients are going to be treated but I think it's as individual as individual centers. What I can tell you, though is to a sense. So they will tell you that they expect to treat the vast majority of those minimal function patients.

Stuart A. Arbuckle: So clearly, the capacity of centers is going to be a challenge. In terms of prioritizing patients, Mike, we've heard just about everything from every different center. I think if you talk to one center, you'll get one response. If you talk to another, you'll get another.

Over time, and indeed expect the vast majority of those who are currently being treated with syndication ORKAMBI all say to transition over time, but the real rates of answer to that is going to be just their ability to process. All of those patients through the limited number of centers that are all freshmen 80.

Stuart A. Arbuckle: Some have said that they will prioritize hep mins, and some have said that they will treat their most severely impacted patients, irrespective of what their mutation is. Others have said they will kind of treat patients as they come in. So I'd love to tell you there's one answer to how patients are going to be treated, but I think it's as individual as individual centers. What I can tell you, though, is that at a center, they will tell you that they expect to treat the vast majority of those minimal function patients over time and indeed expect the vast majority of those who are currently being treated with Symdeco and Orkambi also to transition over time. But the real rate limiter for that is going to be just their ability to process all of those patients through the limited number of centers that there are in Reshma, AAT

Right.

With regard to the 80 workshop that took place just a couple of months ago.

Really pleased to be there it was nice to be invited to me with the communication with the agency.

That the there was real recognition of the disease, the grabbing if the disease and the high unmet need.

It was also interesting to see that our approach as small molecule corrector remains the only one that holds the potential to treat the liver lung disease.

With regard to where the agency is I found them to be.

Very open minded and acknowledge that the.

The in the augmentation companies today has gotten the approvals based on 80 levels and that's that data point that's there.

As also encouraged by their comments that they're going to work with each individual sponsor based on their approach to determine exactly what the phase three trials could look like.

Reshma Kewalramani: Right. With regard to the AAT workshop that took place just a couple of months ago, we were really pleased to be there. It was nice to be invited to be with the community and with the agency. I thought that there was real recognition of the disease, the gravity of the disease, and the high unmet need. It was also interesting to see that our approach, a small molecule corrector, remains the only one that holds the potential to treat both the liver and the lung disease. With regard to where the agency is, I found them to be very open-minded and acknowledged that the augmentation companies to date have gotten the approvals based on AAT levels, and that's the data point that's there. And I was also encouraged by their comments that they are going to work with each individual sponsor based on their approach to determine exactly what the phase three trials could look like.

Okay. Thank you.

Thank you.

Not all of Cowen and company.

Earlier there.

And Philip.

Please.

And our next question comes from Alethia Young of Cantor Fitzgerald.

Ben.

Hey, guys. Thanks for taking my.

Question and congrats on all the progress you've made.

I guess I, just kind of two I wanted you to talk a little bit about somebody on how it fits in your welding medicines, but still at the kind of a much bigger addressable market and different angle from where you guys are going and it separately like in the United Kingdom. I know there you said 5000 do you think there's like a scenario where people there'll be some sort of controls as far as you know kind of I wouldn't say all the patients are aware.

How to some degree the inkatha management they might happen there that we should think about air model. Thanks.

Reshma Kewalramani: Thank you. Thank you, and our next question comes from Phil Nadeau of Cowen & Company. Your line is now open. Phil, are you there? And Phil, if your phone is on mute, please unmute it.

Yes. Thanks, we view this is Jeff I'll take the Semih question and then Stuart will take the question.

With regard to summer I have to start off reminding you that type one diabetes is a disease that fits our strategy currently right. It's a serious disease by 1.25 million patients in the U.S. treated in a relatively small number of centers by endocrinologists are you can certainly reach them with a specialty sales.

Geoff Meacham: And our next question comes from Alethea Young of Cantor Fitzgerald. The line is now open. Hey guys, thanks for taking my question and congrats on all the progress you've made. I guess I kind of, too, I wanted you to talk a little bit about the SEMA deal and how it fits in with your world of innovative medicines, but still, it's kind of a much bigger addressable market and a different angle from where you guys are going. And, you know, separately, like in the United Kingdom, I know there are, you know, 5,000 patients in the UK. Do you think there's a scenario where people, there'll be some sort of controls as far as, you know, kind of, I would assume all the patients are warehoused to some degree?

Force and interestingly. Despite the fact that you know as Lynn has been around it has saved their lives for almost 100 years, though it turns out that insulin therapy for these these type one patients.

Not really a very good long term way of returning them to normal garcinia, our normal hemoglobin levels and so they as you know suffer from very high rates of cardiovascular disease as well as from multiple hypoglycemic episodes. So there's a large unmet need obviously with the first patient subset and it fits our strategy.

Dr. Jeff Leiden: Yeah, thanks, Levi. This is Geoff. I'll take the STEMA question, and then Stuart will take the England question.

We also new for more than 15 years that if you can successfully transplant island into these patients you can essentially cure the disease. There were a number of studies of small numbers of patients who were transplanted who cares varick iOS other immunosuppression and many of those patients were not only shares there were.

Dr. Jeff Leiden: With regard to STEMA, I just start off reminding you that type 1 diabetes is a disease that fits our strategy perfectly, right? It's a serious disease. About 1.25 million patients in the U.S. are treated in a relatively small number of centers by endocrinologists, so you can certainly reach them with a specialty sales force.

Long term jurors some of those patients more of a decade.

Dr. Jeff Leiden: And interestingly, despite the fact that insulin has been around and has saved their lives for almost 100 years now, it turns out that insulin therapy for these type 1 patients is not really a very good long-term way of returning them to normal glycemia or normal hemoglobin A1C levels, and so they, as you know, suffer from very high rates of cardiovascular disease, as well as from multiple hypoglycemic episodes. So there's a large unmet need, obviously, for this patient subset, and it fits our strategy. We also knew for more than 15 years that if you could successfully transplant islets into these patients, you could essentially cure the disease. There were a number of studies of small numbers of patients who were transplanted with cadaveric islets under immunosuppression, and many of those patients were not only cured, but they were long-term cures. Some of those patients had been out for more than a decade.

So there were really two issues with type one diabetes and we've been watching it as one of our views of interest for some time.

I'd say, obviously, David Altshuler is that of apologists as was the geneticists So Houston keenly interested in this disease.

The two problems were there weren't enough Cat America, iOS, and so you need a different way to make islands.

The other problem was the need for immunosuppression was potentially limiting the number of patients you can reach so we were watching companies were addressing those two problems for the last two three years and over the last six months. We were convinced that Semih has actually saw both of those problems. So.

The first thought they have figured out how to take yes cells already but I guess, he sells and successfully differentiate them into human human cells.

Industrial fashion, so they can make industrial levels of.

Of human Islands, and they've shown that those eyelets, an animal models actually are able to cure diabetes, whether transplant. So that was the solution of the number problem and then they have also invented a device that is able to in which you can put the islands, that's able to protect them from the immune response and.

Dr. Jeff Leiden: So there are really two issues with type 1 diabetes, and we've been watching it as one of our diseases of interest for some time. I'd say, obviously, David Altshuler is a diabetologist as well as a geneticist, so he's been keenly interested in this disease. And the two problems were there weren't enough cadaveric islets, and so you needed a different way to make us. And the other problem is that the need for immunosuppression is potentially limiting to the number of patients that you can reach. So we have been watching companies who have been addressing those two problems for the last two, three years, and over the last six to eight months, we have been convinced that FEMA has actually solved both of those problems. So on the first front, they have figured out how to take ES cells or even iPSC cells and successfully differentiate them into human islets, these are human cells, in an industrial fashion, so they can make large amounts of human islets, and they have shown that those islets in animal models are actually able to cure diabetes when they are transplanted.

So some are really has to products. They have what we call naked eye of the bacon transplant into the liver just like Canada. Eric Islands are translated into the liver that does require immuno suppression and they have a second product, which is the island in the device, which we believe can be transplanted ultimately without immunosuppression and that obviously opens up.

The number of patients being treated substantially so in summary, as a disease that fits our strategy perfectly of specialty disease, It's a disease of high unmet need and it's a season, which these recent scientific breakthroughs and given a new approach towards a transformative therapy, so perfect fit and when we saw that we're able to move pretty quickly.

Elite there on expectations for England, I'll, Let me go back to kind of what I said earlier about uptake in all markets. As you said, there's about 5000 eligible patients.

Dr. Jeff Leiden: So that was the solution to the islet number problem. And then they have also invented a device that is able to put the islets in, And so Semra really has two products. They have what we call naked islets that they can transplant into the liver just like catabaric islets are transplanted into the liver. However, that does require immunosuppression. And they have a second product, which is the islets in the device, which we believe can be transplanted ultimately without immunosuppression. And that obviously opens up the number of patients that could be treated substantially. So, in summary, it's a disease that fits our strategy perfectly. It's a specialty disease. It's a disease of high unmet need, and it's a disease for which recent scientific breakthroughs have given a new approach to transformative therapy. So it was a perfect fit, and when we saw that, we were able to move pretty quickly.

In England for the various medicines across the various age range isn't genotypes that are included in the agreement we struck with the NHS. If you look at the uptake rates around the world for those products across patients genotypes, an age ranges, it's as I said in the 80% to 90% range in terms of how many.

You have those patients.

And initiated in similar markets around the world.

Again, not every patient can stay on the medicine, the persistence rates again, I'll somewhere in the 80% to 90% range. So.

If you factor those two things and I think about where might we be when we get to kind of steady state.

Then that could be somewhere around three at a high thousand patients could be persistent on a C. F. T. R. Modulator. If you just take those assumptions I cannot pay the midrange all of those other markets around the world.

Stuart A. Arbuckle: and Alethea on expectations for England. I'll really go back to kind of what I said earlier about uptake in all markets. As you said, there are about 5000 eligible patients in England for the various medicines and across the various age ranges and genotypes that are included in the agreement we struck with the NHS. If you look at the uptake rates around the world for those products across patients and genotypes and age ranges, it's, as I said, in the 80 to 90% range in terms of how many of those patients have been initiated in similar markets around the world. Again, not every patient can stay on the medicine. The persistence rates are again somewhere in the 80 to 90% range.

In terms of warehousing that in something that Weve heard as discussed in the UK, obviously, there's been a lot of.

Pent up demand for these products and so we've heard about people wanting to be initiated I've not heard of people, saying that they're likely to warehouse that patients in anticipation of the triple clearly thats something that could happen as I say, it's not something that I've heard talked about in the UK.

Thank you.

Yes.

Great.

Yeah.

No.

Stuart A. Arbuckle: So if you factor those two things in and think about where we might be when we get to kind of steady state, then that could be somewhere around three and a half thousand patients could be persistent on a CFTR modulator if you just take those assumptions and kind of pick the mid-range of all of those other markets around the world. In terms of warehousing, that isn't something that we've heard discussed in the UK. Obviously, there's been a lot of pent-up demand for these products, and so we've heard about people wanting to be initiated. I have not heard of people saying that they're likely to warehouse their patients in anticipation of the triple. Clearly, that's something that could happen. As I say, it's not something that I've heard talked about in the UK.

Hey, good afternoon, guys. Thanks for taking my questions.

Ill ask one about one of the few countries you don't have a formal agreement in.

Brad So can you remind us how many patients are already on one of your approved CF drugs over there and how we should think about revenue recognition once that deal ultimately comes through in that country.

On the pipeline side regarding CTX 001 for beta fell in sickle cell are you able to elaborate at all on that type of data. We could expect to see later this year in terms of patient numbers or duration a follow up you would have at that point. Thanks.

Core it's Stuart I'll start on on France.

Stuart A. Arbuckle: Thank you. And our next question is from Corey Casamoff with J.P. Morgan. Your line is now open. Hey, good afternoon, guys.

Youre right, France is one of the few markets now where we don't have a reimbursement agreement in place. We are in very active discussions with the French authorities and I'm certainly hopeful that we'll be able to bring those discussions to a successful conclusion as we have recently in Spain in Scotland in England and.

Stuart A. Arbuckle: Thanks for taking my questions. I'll ask one about one of the few countries you don't have a formal agreement in yet, France, so can you remind us how many patients are already on one of your approved CF drugs over there and how we should think about revenue recognition once a deal ultimately comes through in that country? And then on the pipeline,

Australia Youre correct. There are a number of patients who are taking ORKAMBI.

In France.

Can be was available through an early access program for patients 12, plus.

Unknown Executive: On the pipeline side regarding CTX001 for beta-phalancyclic cell

And within the French system. That's approximately 1100 also patients who are currently receiving.

Reshma Kewalramani: Are you able to elaborate at all on the type of data we could expect to see later this year in terms of patient numbers or duration of follow-up you would have at that point?

All camby.

Stuart A. Arbuckle: Corey, it's Stuart. I'll start with France. You're right, France is one of the few markets now where we don't have a reimbursement agreement in place. We are in very active discussions with the French authorities, and I'm certainly hopeful that we'll be able to bring those discussions to a successful conclusion as we have recently done in Spain and Scotland and England and Australia. You're correct, there are a number of patients who are taking Orkambi in France. Orkambi was available through an early access program for patients 12 plus, and within the French system, there are approximately 1,100 or so patients who are currently receiving Orkambi. In terms of revenue recognition and how that might change, I'll turn that over to Charlie.

Terms of revenue recognition and how that might change all I'll turn that over the Charlie Yes core as Charlie for for revenue recognition, we have been recording revenue at a relatively low value for sales into France. Currently when we land on an agreed upon price we will book a catch up of prior period revs.

No, which will equal the difference between the negotiated price and the price at which we have been booking revenue that revenue as it comes through the prior period revenue our intention would be to non-GAAP that out as they won't repeat.

Then going forward, we'll book revenue at the contracted price.

Quite with regard to CTX here is there one and the beta thalassemia and sickle cell program, Here's kind of where we are we have about half a dozen sites open for beta thal about sites open for sickle cell. The studies are enrolling I think you must have heard our partner.

Charles F. Wagner: For revenue recognition, we have been recording revenue at a relatively low value for sales into France currently. When we land on an agreed-upon price, we will book a catch-up of prior period revenue, which will equal the difference between the negotiated price and the price at which we've been booking revenue. That revenue, as it comes through the prior period revenue, our intention would be to non-gap that out, as obviously it won't repeat, and then going forward, we'll book revenue at the contracted price.

And Chris Fair.

Comment on the fact that we will be any position to shared data this quarter.

I think what you should expect to see is safety and Tolerability first and foremost surprisingly.

Phase one two study and on the efficacy side, certainly hemoglobin levels hemoglobin levels will be very interesting amongst other things.

Okay, great. Thank you very much.

Yes.

Thanks.

Yes.

No.

Reshma Kewalramani: Corey, with regard to CTX-001 and the beta-file semia and sickle cell programs, here's kind of where we are. We have about half a dozen sites open for beta-file, and about a dozen sites open for sickle cell. The studies are enrolling. I think you must have heard our partners at CRISPR comment on the fact that we will be in a position to share data this quarter. I think what you should expect to see is safety and tolerability, first and foremost, unsurprisingly, in this Phase I-II study. And on the efficacy side, certainly hemoglobin levels, and hemoglobin F levels will be very interesting, amongst other things.

Great. Thanks, so much in congrats.

I have a couple of questions.

C and one on the triple.

UK.

On 80 I was wondering if you could talk a little bit about the mechanics.

Good thing to corroborate functionality.

Levels produced.

I guess accreted how important is that.

From.

The topline read out and validated.

And then as far as.

Yes.

Reshma Kewalramani: Okay, great. Thank you very much.

You could just give us the latest on where your conversations are regarding reimbursement for the triple and whether or not an agreement there.

Unknown Executive: Thank you, and our next question comes from Paul Mattis of C4, your line is now open, on the triple in the UK. On AAT, I was wondering if you could talk a little bit about the mechanics of the assay you're using to corroborate the functionality of the AAT levels produced by VX814, I guess secreted. How important is that assay and the output from it to the top line readout and to validating the efficacy of the drug? And then, as far as discussions with NHS go, Stuart, I was wondering if you could just give us the latest on where your conversations are regarding reimbursement for the triple and whether or not an agreement there is gated by EMA approval. Thanks so much.

Gated by you may approval. Thanks, so much.

Sure sure. This is freshman let me tackle the 80 hour asked a question so as you've seen our data in the animal models you will remember the slide to the left panel shows you what happens with a b exceed one for AD with VX 86.

Fourth treatment and then Y axis, there is actually functional 80 level. So what we've been measuring in the animal studies is what we will be measuring in the human studies and it's.

Reasonably.

At easy.

I would like to say easy in terms of a clinical trial, but it's a it's a reasonably simple assay and it's the same functional assay that you've seen us deal with the animal studies.

Reshma Kewalramani: Sure, sure. This is Reshma.

Reshma Kewalramani: Let me tackle the AAT assay question. So, as you've seen our data in the animal models, you'll remember the slide on the left panel shows you what happens with VX814 and with VX864 treatment, and the y-axis there is actually functional AAT levels. So, what we've been measuring in the animal studies is what we will be measuring in the human studies, and it's a reasonably easy, I never like to say easy in terms of a clinical trial, but it's a reasonably simple assay, and it's the same functional assay that you've seen us do in the animal studies.

Yes, Paul.

On the UK just to be Crystal clear the current agreement the one that we announced last week. The current commercial agreement does not include the Triple combination. This includes kalydeco and its approved indications ORKAMBI and some Kevin. So triple is not included obviously, there's a very high level of awareness of the triple.

Combination both in the CF community and the NHS E.

But access to the medicine in the UK is going to be.

Governed by our ability to get DNA approval in the first instance.

Reshma Kewalramani: Yeah, Paul, just on the UK, just to be crystal clear, the current agreement, the one that we announced last week, the current commercial agreement, does not include the triple combination. It includes Kalydeco and its approved indications, Orkambi and Simkevi, so triple is not included. Obviously, there is a very high level of awareness of the triple combination, both in the CF community and at NHS E. But access to the medicine in the UK is going to be governed by our ability to get EMA approval in the first instance.

Yeah.

Question time.

Not all of Cowen and company your line is open.

Thanks for taking my question, sorry, but before if it goes on mute.

First on the trick after launch in the U.S. I think you've mentioned a couple of times that capacity will be limiting.

Getting getting new patients on therapy do you have a sense of exactly what the capacity is that CF centers, how many patients.

Stuart A. Arbuckle: Thank you. And our next question comes from Phil Sattel of Cowan & Company. Your line is now open. Good afternoon. Thanks for taking my question. Sorry about before; I think I was on mute.

Good to see their physician every month every quarter every year.

During 2020.

Yes, Bill it's due again capacity as CF centers is we have from the CF centers.

Unknown Executive: First, on the Trikafta launch in the U.S., I think you've mentioned a couple times that capacity will be limiting to getting new patients on therapy. Do you have a sense of exactly what that capacity is at CF centers? How many patients could see their physicians every month, every quarter, every year?

All the time, we heard it in the run up to the.

Launches of ORKAMBI and same Kevin we've heard it went talking to them about how that planning to approach. The Oh the launch of try CAFTA essentially the real uptick step that just to be clear is it's the same 275 cents as you are seeing.

Stuart A. Arbuckle: Yeah, Phil, it's Stuart. Yes. Capacity at CF centers.

All of their CF.

Stuart A. Arbuckle: C.F. centers all the time. We heard it in the run-up to the launches of Orkambi and Simkevi, and we heard it when talking to them about how they're planning to approach the launch of Trikafta. Essentially, the reluctant step there, just to be clear, is it's the same 275 centers who are seeing all of their C.F. patients, and whilst there is a huge amount of enthusiasm about Trikafta, they've got other patients who are coming in for their regular visits. They've got patients who are not yet eligible for Trikafta. Obviously, they've also got people, sadly, who are being admitted with exacerbations and things like that. So, whilst Trikafta is very, very important to them, they have a lot of other things that are going on as well.

Patients and while there is a huge amount of enthusiasm about trike. After they've got other patients who are coming in for that regular visits the Gulf.

Patients who are not yet eligible to try cap. There. Obviously that also got people sadly who are being admitted with exacerbations and things like that so.

While strike after is a very very important to them. They have a lot of other things that are going on as well as I said in total there is 18000 patients who are eligible for try catheter in the United States, who will be treated at the 275 or so CF centers.

As I said it was about 800000 patients who are eligible for ORKAMBI about 12000 full us and Kevin. So that's why we think whilst we think we're going to get to very high levels of uptake overall over time. It may be that it takes us a little bit longer to get to those kind of peak levels of the uptake than it did with ORKAMBI.

Stuart A. Arbuckle: As I said, in total, there are 18,000 patients who are eligible for Trikafta in the United States who will be treated at the 275 or so C.F. centers. As I said, it was about 8,500 patients who were eligible for Orkambi, and about 12,000 for Simkevi. And so, whilst we think we're going to get to very high levels of uptake overall over time, it may be that it takes us a little bit longer to get to those kind of peak levels of uptake than it did with Orkambi and Simkevi.

Some Kevin.

Got it okay. Thank you.

Good question, just a follow up to Paul's part question on the UK The press reports.

The current agreement that you have mentioned that.

In order for the triple to be reimbursed in the UK it will be subject to a nice.

And evaluation by nice.

Look a little bit more about their processes that different process than what you've had before to secure reimbursement or.

Is the triple kind of starting from.

From.

Floor and need to go through the whole process that you're ministers have had to go through the past.

Stuart A. Arbuckle: In the past?

Stuart A. Arbuckle: Yeah, great question, Phil. So, yes, we will be submitting the triple combination to NICE, pending an EMA and CHMP positive recommendation. We've said that we will submit that and discuss the timing of when we will submit that with the NHS and NICE. And we've agreed, and we made public that we are planning to do that around January 2021. The reason for that is a couple of folds. One, it will allow us to collect additional long-term data as we are currently doing in the US through our open label extension studies. And we know how important that long-term data is in terms of demonstrating the benefit of CFTR modulators. We've seen that with Kalydeca, we've seen that with Orkambi, and now with Simkevi.

Yes, great question, Phil So.

Yes, we will be submitting the triple combination to nice pending M&A and CH MPV positive recommendation.

We said that we will submit that discussed the timing of when we will submit that with the NHS and nice and Weve agreed and we made public that we are planning to do that in around January 2021.

The reason for that is a couple of fold won.

That will allow us to collect additional long term data as we are currently in the us through our open label extension studies that we know how important long term dates or is in terms of demonstrating the benefit of see FCL modulators, we've seen that with Kalydeco, we're seeing that with ORKAMBI analysis and Kevin.

Stuart A. Arbuckle: The more data we get, the more you get to see the long-term benefits these types of agents have. The second reason why that timing, we think, is an appropriate time to be submitting is that NICE is currently undergoing a review of its methodology. As you may know, and as we've made quite public, we have some concerns about the approach that NICE takes to evaluating medicines in terms of their ability to truly value appropriately medicines like ours that have the kinds of long-term benefits that ours have. And we're hopeful that, through that methods review, there may be some changes to the evaluation methodology that allow them to better value the types of benefits that our medicines bring. So we've committed to submitting the triple. January 2021 is when we have said that we will do that. And hopefully, that's explained.

The more data we get the more you get to see the long term benefits. These types of agents have.

The second reason why that timing, we think is.

I'm missing is the nice is currently undergoing a review of its methodology.

As you May know and as we've made quite public we have some concerns about the.

Approach that nice takes to evaluating medicines in terms of their ability to truly value appropriately medicines like almost half the kinds of long term benefits that AWS half.

We are hopeful that through that methods review that they may be some changes to the evaluation methodology, which allow them to better.

Value the types of benefits that all medicines bring so we've committed to submitting the Triple January 2021 is when we've said what we will do that and hopefully that's explained the reasons why we.

Stuart A. Arbuckle: We've agreed on that timeline.

Agreed on that timeline.

Stuart A. Arbuckle: Perfect. That's very helpful.

Reshma Kewalramani: Thanks for taking my questions. Thank you. And our next question comes from Matthew Harrison of Morgan Stanley. Your line is now open. Hey, Greg, good evening. Thanks for taking the time to answer the question. I was hoping maybe we could spend a minute on 147. Can you just talk about exactly what data you expect to have available next year? And, you know, given that data, I assume on, you know, some renal parameters, what would you expect to look at in terms of the next study?

That's very helpful. Thanks for taking my questions.

Yeah, and then next question comes from Matthew Harrison at Morgan Stanley . Your line is open.

Hey, great. Good evening. Thanks for taking my question I was hoping maybe you can spend a minute on on one or seven can you just talk about exactly what data you expect have available.

Next year and given given that data I assume on some renal parameters.

What you expect to look at in terms of an exciting.

Reshma Kewalramani: Sure.

Reshma Kewalramani: So, just to catch everybody else up to speed on VX147, this is the molecule that's targeted at the APOL1 axis, and there is a known disease called FSGS, focal and segmental glomerular sclerosis, a type of kidney disease that unfortunately is relentless and really has only one outcome, and that is progression to either end-stage renal disease, transplant, or death. It's really a very serious kidney The way it manifests itself is proteinuria, that is to say, protein in the urine.

Sure.

So just to catch everybody else up to speed on VX. One for seven this is the molecule that is targeted at the April one access and there is.

There is a known disease called Fscs, Opel and segmental Glomerulosclerosis a type of kidney disease that Unfortunately is relentless and really has only one outcome and that is progression to either end stage renal disease transplant or death, it's really.

A very significant renal disease the weight manifests itself. It's proteinuria that is to say protein engineering, So where we are right now with the VX. One for seven program is where in phase one doing the fact, Matt we anticipate that we're going to be ready to go to phase to the dose ranging study next year 2020.

Reshma Kewalramani: So, where we are right now with the VX147 program is that we're in phase 1 doing SAG-MAD. We anticipate that we're going to be ready to go to phase 2, the dose-ranging study next year, 2020. And while it's too early to call exactly when we're going to have results, I expect it to be a very modest-sized study given the small patient population that has this disease and the very grievous nature of the disease. So in that dose-ranging study that'll get off and running in 2020, I anticipate the end point there is going to be proteinuria, which is very convenient because that is the end point of significance, and it is the proof of biological activity.

And while it's too early to call exactly when we're going to have results are expected to be a very modest sized study given the small patient population that has this disease and the very grievous nature of the disease.

So in that dose ranging study that will get off and running in 2020 I anticipate.

The end point, there is going to be proteinuria, which is very convenient because that is the endpoint of significance and it is the proof of biological activity.

Reshma Kewalramani: I should be the one to talk about the others.

The other.

Reshma Kewalramani: Oh yes, sure, sure.

Oh, yes sure sure.

Reshma Kewalramani: You know, just like in cystic fibrosis and what you've seen us do there, we have a portfolio of molecules for this as well, for the APOL1-mediated kidney diseases. So while VX147 is the one that's in the lead and going through its sad math, there's a whole portfolio of molecules behind that in late preclinical, and those will also be making their way through the clinic.

You know just like in cystic fibrosis, and what you've seen US do there we have a portfolio of molecules for this as well for the April one mediated kidney diseases. So while VX one for seven is the one that in the lead and going through with that Matt There's a whole portfolio molecules.

Behind that in late preclinical and those will also be making their way through the clinic.

Thanks.

Reshma Kewalramani: Thank you. And our next question comes from Brian Abrahams, RBC Capital Markets. Your line is now open. Hi, thanks so much for taking my questions and congratulations on all the progress. Two questions for me on Trikafta.

And our next question comes from Brian .

The capital markets. Your line is open.

Hi, Thanks, so much for taking my questions and congratulations on all the progress.

Two questions for me on track have to I guess first off just given how early this was approved anything that you guys need to do in parallel more than typical post marketing clinical work preclinical toxicology maintain it on the on the market and then any education awareness that you plan to do around some of the side effect nuances versus or can be or seem to go.

Brian Abrahams: I guess first off, just given how early this was approved, anything that you guys need to do in parallel more than typical post-marketing, clinical work, preclinical toxicology, or CARC to maintain it on the market? And then any education or awareness that you plan to do around some of the side effect nuances versus or can be or seem to go? I'm sort of curious how we should think about compliance and persistence ending up given the cocktail's overall benefit risk, maybe relative to, say, sim to go. Thanks.

I'm sort of curious how we should think about compliance and persistence ending up given the cocktails overall benefit risk maybe relative to say seem to go. Thanks.

Reshma Kewalramani: Sure, let me start us off and then I'll ask Stuart to comment on education and on compliance persistence. So obviously, we were thrilled with the quick approval of Trikafta and I do think it reflects the benefit and the very nice tolerability of this medicine. With regard to what to expect in the post-marketing setting, nothing really unusual or different. You know that we have a study in F-gating and FRF patients that we have already initiated, so those are continuing, but no, nothing else that's different or unusual.

Sure, Let me start us off and then I'll ask you want to comment on.

Education, then on compliance persistence. So obviously, we were thrilled with the quick approval of try Catherine I do think it reflects the.

The benefit and the very nice Tolerability of this medicine with regard to what to expect in the post marketing setting nothing really unusual or different you know that we have a study in F. Gating FRS patients that we had already initiated so those are continuing but no nothing.

Yes, that's different or unusual Stuart.

Stuart A. Arbuckle: Stuart?

Brian Abrahams: Yeah, Brian, in terms of Trikafta and its benefit-risk profile, as you would expect, we will be being as fulsome as we can in our discussions with physicians on both the benefits of the molecules and the adverse events that we've seen from the studies. As you know, the benefit-risk profile is very positive as a result of that in terms of what we expect.

Yes, Brian in terms of try Capterra and its benefit risk profile as you would expect we won't be being as fulsome as we cannot discussions with the.

Physicians on both the benefits of the molecules and the adverse events that we've seen from the studies as you know the benefit risk profile.

Is very positive as a result of that in terms of what we expect in terms of compliance rates I would expect them to be very high just as they have been with our other cfd all modulators as I.

Stuart A. Arbuckle: In terms of compliance rates, I would expect them to be very high, just as they have been with our other CFTR modulators. As I mentioned earlier, we see them in a very tight range across Orkambi, Symdeco, and Kalydeco. They're in that sort of 80% to 85% range in terms of compliance with the medicine. Given the benefit-risk profile that we've seen with Trikafta, I would expect it to be right in that range, if not towards the top end of that range. Obviously, we'll see how it plays out in the real world, but that would be my expectation.

I mentioned earlier, yeah, we see them in a very tight range across ORKAMBI syndicated show and Kalydeco there in that sort of 80% to 85% range in terms of compliance with the madsen given the benefit risk profile that we've seen with try CAFTA I would expect it to be right in that range, if not towards the top end of.

That range, obviously, we'll see how it plays out in the in the real world, but that would be my expectation.

Thanks, so much.

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

Thank you.

Jeff.

Okay.

Geoff Meacham: Hey guys, thanks for the question and big congrats on the fast approval of Trikafta. So a question for Stuart, for the rollout, I guess one of the lessons that you guys have learned with getting reimbursement secured, you know, with Kaleidiko, say, going back years ago or Symptico more recently, is really focused on how you can reduce the insurance access barrier. So that's question one. And the second is... What percent, roughly, would you assume need some sort of copay assistance, and what are you guys doing about that?

Hey, guys. Thanks for the question Big Congrats on the on the fast approval of try CAFTA.

So a question for Stuart.

The rollout I guess, where the lessons that you guys have learned with getting reimbursement secured with Classico say going back years ago or some dako more recently.

That's really focus on how you can reduce C insurance access barrier. So that's question one in the second is.

What percent of roughly would you assume need some sort of co pay assistance and.

What are you guys doing for that and I have a follow up.

Stuart A. Arbuckle: Yeah, so Geoff, in terms of, you know, what we've learned in terms of getting access here in the U.S., I would say, going back all the way to Kalydeco through Orkambi and Syndico, we've seen very broad reimbursement, and actually, that reimbursement has been put in place pretty quickly. Now, obviously, there is a range across all of the government and commercial payers, and so some move faster than others, some move slower than others, but in general, we've seen them move pretty quickly, and we've ended up with kind of rapid and broad reimbursement.

Yes, Jeff in terms of.

What we learn.

In terms of.

Getting access here in the US I would say going back all the way to Kalydeco through ORKAMBI and I'm sitting to go we have seen very broad reimbursement and actually the that reimbursement has been put in place pretty quickly now obviously, it's a range across all of the government and.

Commercial payers and so some move faster than others, so move slower than others, but in general we've seen them move pretty quickly and we've ended up with kind of rapid and broad.

Reimbursement I think the thing that gives me hope that that will happen is obviously, we've been out there with these payers now for seven years in the U.S. They have a very very good sense all how severe this disease is.

Stuart A. Arbuckle: I think the thing that gives me hope that that will happen is obviously we've been out there with these players now for seven years in the U.S. They have a very, very good sense of how... very well prepared to secure broad access.

The benefits that all mentioned the fab and the team is is out there now token we pay and today as I say in terms of the reaction. We've had the reaction today has been very costly. So I feel very good that our team is.

Stuart A. Arbuckle: In terms of insurance barriers, yes, there will always be some. We have a great team here who is trained to do just this, to help patients out, and provide support to them as they navigate the insurance barriers. In terms of what we are going to do to support those patients who may have financial needs, we have the standard suite of offerings that you would expect, and certainly, our commitment is that we are going to do everything we can to make sure that no patient is left behind because of their ability to pay.

Very well prepared to secure broad access in terms of insurance berries, yet, yes, there will always be so we have a a great team here, which is trained to do justice to help patients out provide support to them as they navigate.

The insurance.

Barriers.

In terms of what are we going to do in supporting those patients you may have a financial needs. We have the standard suite of offerings that you would expect and certainly our commitment is that we are going to do everything we can to make sure that no patient is left behind because of their ability to pay.

Dr. Jeff Leiden: Okay, and then just a follow-up question for Reshma or maybe even Geoff, when you think about opportunities to diversify outside of CF, you guys have a lot, and it seems like Aaron's been working pretty hard, but beyond the pain program, most of them are early, though, so I wanted to ask you, you know, what's the capacity or even how much of a priority is bringing on later stage assets as you Thank you.

Okay.

Then and then just a follow up for ratio or maybe even Jeff when you think about opportunities to diversify outside of see after you guys have a lot and it seems like aronson working pretty hard.

But the pain program.

Most of them or early though so I want to ask you know, what's the capacity or even how much of a priority is bringing on later stage assets.

As you begin to see the leverage in the piano from the truck after launch thank you.

Dr. Jeff Leiden: It's a great question, Geoff. Maybe I'll take that one.

It's great question, Jeff maybe I'll take that one.

Dr. Jeff Leiden: We have been working hard, the entire team, on getting these deals done. I was showing our board today that I think we've done more deals in 2019 than we did in 2016, 17, and 18 combined. And that's a good thing, obviously.

We have been working hard at higher team on.

Im getting these deals I was showing our board today that I think we've done more deals of 2019 than we've done than we did in 2016 17 18 combined so thats a good thing obviously, we have well diversified our pipeline and we've also considerably filter toolbox and you should expect to see US continue to do that I think we've been pretty consistent all along and.

Dr. Jeff Leiden: We have, quote, diversified our pipeline, and we've also considerably built our toolbox. And you should expect to see us continue to do that. I think we've been pretty consistent all along in saying what you probably shouldn't expect to see us do is to buy on-market assets or very late-stage assets to essentially buy revenue growth. We don't really need revenue growth. Our CF franchise will provide that well into the 2020s. And so we're in a very nice position of being able to invest in earlier-stage assets where, by the way, we think we can get much better value and also add much more value from our own internal development and regulatory group so that we can build much, much better value both for patients and for shareholders. And so you should expect to see us continue to do deals, early-stage assets where we can add value, technologies, particularly ones that bolt onto our gene editing strategy, which, as you know, we have brought and sort of built over the last couple of years.

Saying, what you probably shouldn't expect to see US too is to buy on market assets are very late stage assets to essentially by revenue growth. We don't really need revenue growth RCR franchise will provide that well in the 20 twond.

In a very nice position of being able to invest in earlier stage assets, where by the way. We think we can get much better value and also add much more value from our own internal development and regulatory group. So that we can build much much better value both for patients in four or.

So you shouldn't expect to see us to continue to do deals early stage assets, where we can add value technologies, particularly that bolt onto our gene editing strategy, which as you know we brought them. So.

After.

Dr. Jeff Leiden: And more of those deals, but I don't think you'll see us do very late stage, certainly not on market products or very late stage products.

And more of those deals, but I don't think you'll see us do the very late stage certainly not on market products are very late stage.

Reshma Kewalramani: I just wanted to add to that. You mentioned the pipeline and where we are. You've already talked about pain. It's actually interesting to know how many molecules we have already in mid-stage development. So, CTX001 is already in Phase I-II. AAT, we expect to be in Phase II, and it'll start this quarter. And FSGS, I expect to be in Phase II next year.

Alex I just wanted to add to that you mentioned the pipeline and where we are you already talked about pain.

It's actually interesting to note how many molecules we have already into mid stage development. So CTX fares here one is already in phase one two and 18, we expect to be in phase two ill start this quarter 2019, and SGS I expect to be in phase two next year.

Liisa Bayko: Great. Okay. Thank you. Thank you, and our next question comes from Liisa Bayko of JMP Security. Your line is now open. Oh, hi. Thanks for taking the question. I just wanted to ask a couple questions about the pipeline.

Great. Okay. Thank you.

Thank you.

Comes from like the bank.

JMP Securities Your line is open.

Hi, Thanks for taking my question I just wanted to ask for a couple of questions about the pipeline. The first is for the 80 program I noticed your focusing on patients with two is the mutations can you maybe just break down.

Reshma Kewalramani: The first is for the AAT program. I noticed you're focusing on patients with 2Z mutations. Can you maybe just break down the AAT population into its kind of mutation types to better understand, you know, what kind of group you're addressing with that small molecule corrector, the first one?

The H T population into its kind of mutation types to better understand you know what kind of a group you're addressing.

With with that small molecule corrector the first one.

Reshma Kewalramani: So you're right that there are different subgroups of patients who have alpha-1 antitrypsin deficiency, but the majority of patients have the Z mutation. The majority of patients who are ill have the Z mutation. So 90% plus have the ZZ mutation. So it's no surprise that that's the group that we're focused on.

So you're right that there are different subgroups of patients who have alpha one antitrypsin deficiency, but the majority of patients have the mutations the majority of patients who are ill have the mutation so 90% plus had the the the mutation. So I was surprised that that.

The group that we're focused on.

All right that makes sense.

And then.

Similar question I know little bit about Fscs.

Reshma Kewalramani: Alright, that might... And then, sort of a similar question, I know a little bit about FSGS. You're kind of qualifying it as mediated by APOL1. Is that, again, the majority of FSGS cases? I'm curious about that one.

You kind of qualifying and as these the.

As mediated by 80 allow one is that there is that again the majority of Fs, Jeff cases that just.

Curious about that one.

Reshma Kewalramani: Sure, sure. But that one's a little bit different. So FSGS is a heterogeneous group of ideologies that result in that. FSGS is actually named after its finding in pathology, but there is a homogeneous group within that, that is mediated by APOL1. So we are not pursuing all FSGS; we are pursuing APOL1-mediated FSGS. It's a group, it's a homogeneous subgroup of all FSGS, and it turns out that there are actually other groups of renal disease that are also mediated by APOL1, but the one we're focused on is APOL1-mediated FSGS.

Sure sure so that was a little bit different so fscs is.

A heterogeneous group of etiologies that with both in that Fscs is actually named after its finding onto pathology.

It's a great homogeneous group within that that is.

Mediated by April one so not pursuing all fscs, we're pursuing April one mediated fscs, it's a group.

Homogeneous subgroup of all of that isn't it turns out that there's actually a other groups renal disease that are also mediated by April one, but the one we're focused on is April our one mediated SGS and the release of because there is very strong human genetics evidence that April one is because of that disease.

Reshma Kewalramani: And the reason is that there's very strong human genetic evidence that ApoL1 is the cause of that disease.

Reshma Kewalramani: Okay, great. And then, I guess, how do you know that the FSGS is related to that? And, I guess, among FSGS patients, what, you know?

Okay, Great and then how I guess, how do you know that the efforts just as it related to that and and and I guess.

The fscs patients what what you know how prevalent as this particular.

Reshma Kewalramani: So, you know, I happen to be a nephrologist, so I really like this topic, but I'll keep it short. And here's what I'll say.

Yeah.

See you know I happen to be Nephrologist, So I really like this topic, but I'll keep it short and here's what I'll say maybe to two three important point to mention our amongst African American patients who have.

Reshma Kewalramani: Maybe the two, three important points to mention are, amongst African-American patients who have FSGS, 70 plus percent have FSGS that's related to ApoL1, so the vast, vast majority. And the only other important point I'll make for today's call is that there are studies, really nicely done studies, that look at patients who have ApoL1-mediated FSGS versus not. Those patients have more serious disease that is more progressive. As Geoff said, it is a causal factor here, and that's why we are so interested in this disease and in this pathway. And the way you know is just by sequencing. This is an allele that's been described.

Fscs 70, plus percent have fscs thats related to April alwan.

So the vast vast majority and the only other important point I'll make for today's call is that there are studies really nicely done studies that look at patients who have April one mediated SGS versus not.

Those patients have more serious disease that is more progressive as Jeff said it is they causal factor here and that's why we're so interested in this disease and in this pathway and the way that was just by sequencing. This was an illegal has been describe the literature. Okay. Great. Thank you.

Reshma Kewalramani: Okay, great. Thank you. Thank you, and our next question comes from Geoff Ford of STC Learing, so on and so forth. Thank you. Thank you very much.

Thank you.

Yes.

I've SDB Larry.

Thank you. Thank you very much just change the direction a little bit of Charlie could you tell us what the free cash flow was in the quarter.

Unknown Executive: Thank you very much and to change the direction a little bit.

And give a little bit more clarification on operating margins and then Stewart.

Charles F. Wagner: Charlie, could you tell us what it is?

Charles F. Wagner: Could you tell us the total number of patients on one of your CF medicines and the breakdown of Kalydeco U.S. sales?

Could you tell us the total number of patients on.

One of your CF medicines, and the breakdown of Kalydeco us.

Charles F. Wagner: Thank you for joining us for the Kaleidoco Acambia and Symdeco, just so we can kind of level set our models. Thanks.

Product ORKAMBI. Some deco just so we kind of level sort of models. Thanks.

Charles F. Wagner: Sure, Geoff, on the free cash flow in the quarter, we can follow up with you afterwards on that. You know, as I highlighted, we ended the quarter with about $4 billion in cash. That did not include the SEMA disbursement for SEMA, which happened shortly after.

Okay.

Sure Jeff on the free cash flow in the quarter, we can follow up with you afterwards on that as I highlighted we ended the quarter with about 4 billion in cash that did not include.

The summer the disbursement for some of which have been shortly after what you can see though with our with our performance. This year is that we're on track to end the year with more cash than we started the year and thats, even after spending nearly $1.5 billion on business development during the year. So the operating leverage in the cash flow generate.

Charles F. Wagner: What you can see, though, with our performance this year is that we are on track to end the year with more cash than we started the year, and that's even after spending nearly $1.5 billion on business development during the year. So, the operating leverage and the cash flow generation continue to be very strong. The second part of your question was around operating margin.

Generation continues to be very strong second part of your question was around operating margin.

Charles F. Wagner: You know, we've run in the kind of low to mid-40s in the first half of the year. We do expect – you saw a little bit of a ramp up in expenses in the third quarter. There was an additional ramp up in the fourth quarter. So, we should end the year in that low to mid-40s range, again, a significant increase over last year, which was around 39 percent.

We've run in the kind of low to mid forties in the first half of the year. We do expect you've seen that you saw a little bit of a ramp up and expenses in the third quarter is an additional ramp up in the fourth quarter. So we should end the year in that low to mid Fortys range again, a significant increase over last year, which was around 39% and so with the continued.

Growth of the business on the top line and disciplined spending we continue to drive operating margins up and you could expect that into 2020 as well.

Charles F. Wagner: And Geoff, in terms of the breakdown, I think it was just Kalydeco.

And Jeff in terms of the and the breakdown all I think it was just Kalydeco you wanted us ex us.

Charles F. Wagner: U.S.

Charles F. Wagner: [inaudible]

The three mark.

Charles F. Wagner: So Kalydeco U.S. was $163 million in the quarter, Ex-U.S. was $87 million, Orkambi was $199 million in the quarter in the U.S., 98 Ex-U.S., and Syndicoe Sinquevee, the U.S. was $349 million, and Ex-U.S. was $55 million in the quarter.

All right I've got all three.

So kalydeco you asked was $163 million in the quarter.

Ex us was 87.

You can be was $199 million in the quarter in the US 98, ex us and syndication can be the U.S. was $349 million, an ex us was $55 million in the quarter.

Charles F. Wagner: And Geoff, this is Charlie. I would add, you've been pretty consistent in looking for the details on this. Going forward, we're going to move away from some of this detail. You know, obviously now with the triple approval, we've got a portfolio of medicines that are going to allow us to treat the vast majority of patients. Within medicines, there is a significant level of label overlap, and we see a significant level of switching and would expect even more switching with the triple. As a result, you know, the very, very detailed breakdown by product becomes less meaningful over time. So, moving forward, our intention would be to report total CF revenues and break that up by product. We will also break out our U.S. and ex-U.S. revenues, but we will move away from providing very detailed product biographies. All right.

Jeff This is Charlie I would add you've been pretty consistent in looking for the detailed on this going forward, we're going to move away from some of this detail obviously now with the Triple approval. We've got a portfolio of medicines that are going to allow us to treat the vast majority of patients within the the medicines. There is a significant level of labor.

Overlap and we see a significant level of switching and would expect even more switching with the triple as a result that did very very detailed breakdown by product becomes less meaningful overtime. So moving forward. Our intention would be to report total CF revenues and break that up by product. We will also breakout our us an ex us revenues.

But we will move away from providing very detailed product biography reps.

Charles F. Wagner: All right, then we'll know what to expect. Thank you.

Well it will know what to expect thank you.

Operator, we have time for one more question.

Unknown Executive: Operator, we have time for one more question.

Unknown Executive: Thank you. And our last question comes from Whitney Igem of Guggenheim. Your line is now open. Hey guys, thanks for taking the questions.

Thanks, Yeah, I know last question comes.

Hi, I'm your line is open.

Hey, guys. Thanks for taking the questions. A couple of quick follow up first on semi they had previously guided to first half 20 start for the naked cell program. I believe is that still on track and then for Fscs. Just curious are there any plans to do sort of a basket study of renal diseases driven by April one.

Whitney Igem: A couple quick follow-ups. First, on SEMA, they had previously guided to a first half 20 start for the Naked Cell Program, I believe. Is that still on track? And then for FSGS, just curious, are there any plans to do sort of a basket study of renal diseases driven by ApoL1? Or, as you mentioned, are you kind of specifically focusing on FSGS for the near term?

Or our Ed you mentioned.

Typically focusing on at yet.

Dr. Jeff Leiden: Yeah, this is Jeff. I'll take the SEMA question, and Reshma will take the FSCS question. In terms of SEMA, we are very pleased with the progress in both programs, the Naked Cells and the Device Plus Cells. I think it's a little early as they're in discussions with regulators to assign a precise date to when they will start clinical trials, but I do anticipate it to be in the near future, meaning this isn't a program that's three to five years out or anything like that. But stay tuned as they and we finish our discussions with regulators. Then we can give you a little more certainty.

For the near term.

Yes, we need this is Jeff I'll take the semi question and national take ever shares question.

In terms of summer, we are very pleased actually with the progress in both programs the naked cells and the device plus so I think it's a little early is there in discussions with regulators to assign a precise data when they will start clinical trials, but I do anticipate it to be in the near future meeting. This isn't a program. It's three to five years out or anything like that.

But the stay tuned as they are we finished our discussions with regulators, we give you a little more certainty.

Reshma Kewalramani: With regard to the FSGS question, it's a good question about basket trials, but no, that's not our approach. The FSGS component compared to, for example, non-diabetic kidney disease that also has an APOL1 mediated component, they're actually different enough that the FSGS patients are much sicker, the progression is faster, and the levels of protein are very high. So we think that there is a real high unmet need there, and we have to go at it first and get there, and then we'll get to the others. So our focus here is FSGS APOL1 mediated, and we're going to do that as a standalone trial.

With regard to the Fscs question.

It's a good question about our basket trials, but no that's not our approach the fscs component compared to for example, non diabetic kidney disease that also has a April one mediated component there actually different enough that the fscs patients are much.

Cash more think the progression is faster and the levels of protein are very high and we think that there is a real high unmet need that we have to.

Go at it first and get there and that will get to the other sharp focus here is fscs.

April one mediated and we're going to do that as Standalone trial.

Unknown Executive: Thank you, everyone. Thank you to the analysts for their questions. If you have additional questions, the Investor Relations team will be available in the office tonight. Have a good evening.

Thank you everyone.

Thanks to the analyst their questions. If you have additional questions. The investor relations team will be available in the obvious Tonight have a good evening.

Unknown Executive: Ladies and gentlemen, this does conclude your hearing, conference call. We now thank you for watching!

Ladies and gentlemen, this does conclude either.

Conference call.

Thanks.

Unknown Executive: BF-WATCH TV 2021