Q4 2023 Vertex Pharmaceuticals Inc Earnings Call

February 5, 2024

Operator: -- question, you may press star then 1 on your touchtone phone. And to withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead, ma'am.

Susie Lisa: Good evening, everyone. My name is Susie Lisa and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our 4th quarter and full year 2023 Financial Results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer and Charlie Wagner, Chief Financial Officer.

Susie Lisa: Financial Officer, we recommend that you access the webcast slides as you listen to this call. The 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 in our filings with the Securities and Exchange Commission.

Financial Officer,

We recommend that you access the webcast slides as you listen to this call. The 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 in our filings with the Securities and Exchange Commission.

Susie Lisa: These statements, including without limitation, those regarding Vertex's marketed medicine for cystic fibrosis, sickle cell disease and beta thalassemia, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented, inclusive of our foreign exchange risk management program

These statements, including without limitation, those regarding Vertex's marketed medicine for cystic fibrosis, sickle cell disease and beta thalassemia, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented, inclusive of our foreign exchange risk management program.

I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented, inclusive of our foreign exchange risk management program

Susie Lisa: Financial results and guidance that we will review on the call. This evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented inclusive of a foreign exchange risk management program I will now turn the call over to Ray Smith.

Financial results and guidance that we will review on the call. This evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented inclusive of a foreign exchange risk management program

program I will now turn the call over to Ray Smith.

program

I will now turn the call over to Reshma.

Reshma Kewalramani: Thanks, Susie. Good evening, all and thank you for joining us on the call today. We delivered another excellent quarter to finish 2023, established a strong foundation for continued growth and started off 2024 with tremendous momentum with additional approvals for CASGEVY, positive Phase III results for VX-548 in acute pain last week and positive results for the VANZACAFTOR Triple Program in CF this afternoon.

Ian F. Smith: Five four rate in acute pain last week and positive results for the vans the captor Triple program in C. F. This afternoon.

Ian F. Smith: In 2023, Vertex continued to reach more CF patients and achieved full-year CF product revenues of $9.87 billion, representing 11% growth versus 2022. Following the historic approvals of CASGEVY, the first ever CRISPR/Cas9-based therapy, our launch is off and running globally. As we are now approved in both sickle cell disease and beta thalassemia in the US, Great Britain, the kingdom of Saudi Arabia and Bahrain. CASGEVY is a one-time, precise,

In 2023, Vertex continued to reach more CF patients and achieved full-year CF product revenues of $9.87 billion, representing 11% growth versus 2022. Following the historic approvals of CASGEVY -- the first ever CRISPR/Cas9-based therapy -- our launch is off and running globally as we are now approved in both sickle cell disease and beta thalassemia in the US, Great Britain, the kingdom of Saudi Arabia and Bahrain. CASGEVY is a one-time, precise, durable CRISPR/Cas9 gene-edited therapy that is generating strong enthusiasm from physicians and patients and excellent support from payers.

Ian F. Smith: Following the historic approvals of cast Gebbie, the first ever Christopher cast mine based therapy or launches often running globally. As we are now approved in both sickle cell disease and beta thalassemia in the U S. Great Britain, the kingdom of Saudi Arabia, and Bahrain cashed Gebbie's a onetime precise.

CASGEVY is a one-time, precise, durable CRISPR/Cas9 gene-edited therapy that is generating strong enthusiasm from physicians and patients and excellent support from payers. We're also working toward multiple additional near-term commercial opportunities, driving toward our five launches in five years goal. The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia, delivered the first two. Now, with the positive Phase III results from VX-548 in acute pain and for the VANZACAFTOR triple therapy in CF, these are potentially the next two.

CASGEVY is a one-time, precise, durable CRISPR/Cas9 gene-edited therapy that is generating strong enthusiasm from physicians and patients and excellent support from payers.

Ian F. Smith: Durable CRISPR Cas nine gene edited therapy that is generating strong enthusiasm from physicians and patients and excellent support from payers. We're also working toward multiple additional near term commercial opportunities driving toward our five launches in five years ago. The recent approvals for cash Chevy.

We're also working toward multiple additional near-term commercial opportunities, driving toward our five launches in five years goal. The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia, delivered the first two. Now, with the positive Phase III results from VX-548 in acute pain and for the VANZACAFTOR Triple therapy in CF, these are potentially the next two. And with a strong clinical stage pipeline with first-in-class or best-in-class assets, we are well on our way to our goal of five launches by 2028.

The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia, delivered the first two. Now, with the positive Phase III results from VX-548 in acute pain and for the VANZACAFTOR triple therapy in CF, these are potentially the next two. And with a strong clinical stage pipeline with first-in-class or best-in-class assets, we are well on our way to our goal of five launches by 2028. In addition to the rapidly advancing clinical stage pipeline,

The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia, delivered the first two. Now, with the positive Phase III results from VX-548 in acute pain and for the VANZACAFTOR Triple therapy in CF, these are potentially the next two. And with a strong clinical stage pipeline with first-in-class or best-in-class assets, we are well on our way to our goal of five launches by 2028.

The recent approvals for CASGEVY in both sickle cell disease and beta thalassemia, delivered the first two.

Ian F. Smith: In both sickle cell disease, and beta thalassemia deliver the first two now with the positive phase III results from VX five for it in acute pain and so the vans the captor triple therapy and C. F. These are potentially the next two.

Now, with the positive Phase III results from VX-548 in acute pain and for the VANZACAFTOR Triple therapy in CF, these are potentially the next two. And with a strong clinical stage pipeline with first-in-class or best-in-class assets, we are well on our way to our goal of five launches by 2028.

Ian F. Smith: And with a strong clinical stage pipeline with first in class or best in class assets, we are well on our way to our goal of five launches by 2028. In addition to the rapidly advancing clinical stage pipeline. The next wave of innovation also continues to make progress and as we announced last month, we are pleased to be advancing to new.

And with a strong clinical stage pipeline with first in class or best in class assets, we are well on our way to our goal of five launches by 2028. In addition to the rapidly advancing clinical stage pipeline.

In addition to the rapidly advancing clinical stage pipeline, the next wave of innovation also continues to make progress. And as we announced last month, we are pleased to be advancing two new disease areas into the clinic. First, myotonic dystrophy type 1 or DM1, a serious disease with high unmet need and no approved therapies. This disease affects approximately 110,000 patients in North America and Europe. Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients. That is to say, a study that we'll be able to assess both safety and efficacy, late last year.

In addition to the rapidly advancing clinical stage pipeline, the next wave of innovation also continues to make progress. And as we announced last month, we are pleased to be advancing two new disease areas into the clinic. First, myotonic dystrophy type 1 or DM1, a serious disease with high unmet need and no approved therapies. This disease affects approximately 110,000 patients in North America and Europe. Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients -- that is to say, a study that we'll be able to assess both safety and efficacy -- late last year.

The next wave of innovation also continues to make progress and as we announced last month, we are pleased to be advancing to new. Disease areas into the clinic first my Atonic dystrophy type one or D. M. One a serious disease with high unmet need and no approved therapies. This disease affects approximately 110000 patients in North America and Europe.

Disease areas into the clinic first my Atonic dystrophy type one or D. M. One a serious disease with high unmet need and no approved therapies. This disease affects approximately 110000 patients in North America and Europe.

This disease affects approximately 110,000 patients in North America and Europe. Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients. That is to say, a study that we'll be able to assess both safety and efficacy, late last year.

Ian F. Smith: Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients. That is to say, a study that we'll be able to assess both safety and efficacy, late last year. And second, we expect to advance into our 10th disease area in autosomal dominant polycystic kidney disease or ADPKD, the most common genetic kidney disease that affects approximately 250,000 patients in the US and EU alone, into the clinic with a healthy volunteer study in the first half of this year.

Our DM1 program represents our ninth disease area to advance into the clinic. We already initiated a Phase I/II study in patients. That is to say, a study that we'll be able to assess both safety and efficacy, late last year.

And second, we expect to advance into our 10th disease area in autosomal dominant polycystic kidney disease or ADPKD, the most common genetic kidney disease that affects approximately 250,000 patients in the US and EU alone, into the clinic with a healthy volunteer study in the first half of this year.

Vance into our 10th disease area in autosomal dominant polycystic kidney disease or a D. P. K D. The most common genetic kidney disease that affects approximately 250000 patients in the U S and EU alone into the clinic with a healthy volunteer study in the first half.

Ian F. Smith: Of this year with that overview, let me now turn to a more detailed pipeline review this quarter I'll limit my comments to the programs with significant recent updates cystic fibrosis sickle cell disease beta thalassemia and pain, so as to leave time for your questions.

Of this year

With that overview, let me now turn to a more detailed pipeline review. This quarter, I'll limit my comments to the programs with significant recent updates -- cystic fibrosis, sickle cell disease, beta thalassemia and pain, so as to leave time for your questions. Starting with cystic fibrosis and our next-in-class VANZACAFTOR Triple Combination therapy. This afternoon, we reported positive results from the Phase III program, including the SKYLINE 102 and 103 studies in patients 12 years and above and the RIDGELINE study in patients ages 6 to 11. We are very pleased with these results and the arc of progress in treating patients with CF as we continue to advance our ultimate goal of bringing all eligible patients to carrier levels of sweat chloride. Treatment with the VANZA Triple met all primary and secondary end points in the three Phase III studies and once again, our proprietary HBE assays, were both qualitatively and quantitatively predictive. In the SKYLINE 102 and 103 trials, the VANZACAFTOR Triple combination met its primary endpoint of non-inferiority versus TRIKAFTA on ppFEV1, consistent with our expectations. The difference in ppFEV1 in the TRI and VANZA-treated groups was negligible. In SKYLINE 102, the LS mean difference was 0.2, numerically favoring VANZA and meeting non-inferiority with a P value of less than <unk>. 0.0001, and then the skylight 103 study again the difference in P. P. F E V. One in the try and vans are treated groups was negligible and numerically favored vans or capture with Alice mean difference of point to meeting non inferiority with.

Ian F. Smith: Starting with cystic fibrosis and our next in class bans a character Triple combination therapy. This afternoon, we reported positive results from the phase III program, including the Skyline 102, and 103 studies in patients 12 years and above and the Ridge line study in patients ages six to 11 and we are.

Ian F. Smith: Very pleased with these results and the arc of progress in treating patients with C. F. As we continue to advance our ultimate goal of bringing all eligible patients to carrier levels of sweat chloride treatment with the vans a triple met all primary and secondary end points in the three phase III.

We are very pleased with these results and the arc of progress in treating patients with CF as we continue to advance our ultimate goal of bringing all eligible patients to carrier levels of sweat chloride. Treatment with the VANZA Triple met all primary and secondary end points in the three Phase III studies and once again, our proprietary HBE assays, were both qualitatively and quantitatively predictive. In the SKYLINE 102 and 103 trials, the VANZACAFTOR Triple combination met its primary endpoint of non-inferiority versus TRIKAFTA on ppFEV1, consistent with our expectations. The difference in ppFEV1 in the TRI and VANZA-treated groups was negligible. In SKYLINE 102, the LS mean difference was 0.2, numerically favoring VANZA and meeting non-inferiority with a P value of less than <unk>. 0.0001, and then the skylight 103 study again the difference in P. P. F E V. One in the try and vans are treated groups was negligible and numerically favored vans or capture with Alice mean difference of point to meeting non inferiority with.

Ian F. Smith: Studies and once again, our proprietary H b assays, where both qualitatively and quantitatively predictive in the Skyline 102, and 103 trials the vans a character Triple combination met its primary endpoint of non inferiority versus tried capped up on P. P.

Ian F. Smith: E V. One consistent with our expectations the difference in P. P. F E V. One in the try and vans are treated groups was negligible in skyline 102. The L. S mean difference was point to numerically favoring banzer and meeting non inferiority with a P value of less than <unk>.

In SKYLINE 102, the LS mean difference was 0.2, numerically favoring VANZA and meeting non-inferiority with a P value of less than 0.0001. And in the SKYLINE 103 study, again, the difference in ppFEV1 in the TRI and VANZA-treated groups was negligible and numerically favored VANZACAFTOR, with LS mean difference of 0.2, meeting non-inferiority with a P value of less than 0.0001. Recall, the improvement in ppFEV1 in treatment-naive patients in the original TRI Phase III program was approximately 14%. In addition, all key secondary endpoints were met across SKYLINE 102 and 103 and showed a statistically significant and clinically meaningful reduction in sweat chloride. The sweat chloride results were measured in three key secondary end points. First, the overall achieve sweat chloride levels and the two RCTs were lower in the VANZA-treated group versus the TRIKAFTA-treated group. The LS mean difference

Ian F. Smith: 0.0001, and then the skylight 103 study again the difference in P. P. F E V. One in the try and vans are treated groups was negligible and numerically favored vans or capture with Alice mean difference of point to meeting non inferiority with.

Ian F. Smith: The P value of less than 0.0001 recall the improvement in P. P. F E V. One in treatment naive patients in the original try phase III program was approximately 14%. In addition, all key secondary endpoints were met across Skyline 102 in one O.

In addition, all key secondary endpoints were met across SKYLINE 102 and 103 and showed a statistically significant and clinically meaningful reduction in sweat chloride. The sweat chloride results were measured in three key secondary end points. First, the overall achieved sweat chloride levels and the two RCTs were lower in the VANZA-treated group versus the TRIKAFTA-treated group. The LS mean difference was -8.4 with a P value of less than 0.0001. In SKYLINE 102, the LS mean difference was -2.8 with a P value of 0.0034 in SKYLINE 103. The key difference, of course, in SKYLINE 102 and 103 was the genotype studied.

Ian F. Smith: AI and showed a statistically significant and clinically meaningful reduction in sweat chloride. The sweat chloride results were measured in three key secondary end points first the overall achieve sweat chloride levels and the two Archie Ts were lower in the vans are treated group versus the truck after treated group the L. S mean different.

Ian F. Smith: Was minus 8.4 with a P value of less than 0.0001 in Skyline 102. The L. S mean difference was minus 2.8 with a P value of 0.0034 in Skyline 103. The key difference of course in Skyline 102, and 103 was the genotype studied.

Ian F. Smith: SKYLINE 102 included FMF patients who have more severe disease and therefore, higher sweat chloride levels at baseline. And SKYLINE 103 included FF and other responsive mutations with lower baseline sweat chloride levels. Next, the second key secondary end point of proportion of sweat chloride, less than 60 millimoles, pooled across two studies. 86% of patients in the VANZA-treated groups and 77% of patients in the TRIKAFTA-treated groups achieved sweat chloride levels below 60 millimoles, leading to an odds ratio of 2.21 and a P value of 0.0001. This means about two times greater likelihood in the odds of achieving sweat chloride less than 60 with VANZA versus TRIKAFTA. Last, the third key secondary end point of proportion of sweat chloride less than 30 millimoles, pooled across the two studies.

SKYLINE 102 included FMF patients who have more severe disease and therefore, higher sweat chloride levels at baseline. And SKYLINE 103 included FF and other responsive mutations with lower baseline sweat chloride levels. Next, the second key secondary end point of proportion of sweat chloride, less than 60 millimoles, pooled across two studies. 86% of patients in the VANZA-treated groups and 77% of patients in the TRIKAFTA-treated groups achieved sweat chloride levels below 60 millimoles, leading to an odds ratio of 2.21 and a P value of 0.0001. This means about two times greater likelihood in the odds of achieving sweat chloride less than 60 with VANZA versus TRIKAFTA.

Ian F. Smith: Millimole pooled across two studies, 86% of patients in the vans are treated groups and 77% of patients in the trial CAFTA Treaty groups achieved sweat chloride levels below 60, millimole, leading to an odds ratio of two point to one and a P value of 0.0001. This mean.

Ian F. Smith: It's about two times greater likelihood in the odds of achieving sweat chloride less than 60 with vans out versus try CAFTA last the third key secondary end point of proportion of sweat chloride less than 30, millimole pooled across the two studies.

Last, the third key secondary end point of proportion of sweat chloride less than 30 millimoles, pooled across the two studies. 31% of patients in the VANZA-treated groups versus 23% of patients in the TRIKAFTA-treated groups achieved sweat chloride levels below 30 millimolars, leading to an odds ratio of 2.87 and a P value of 0.0001. This means about three times greater likelihood in the odds of achieving sweat chloride less than 30 with VANZACAFTOR versus TRIKAFTA. The results were even more pronounced in the RIDGELINE study evaluating children ages 6 to 11. The primary endpoint in this single arm study was safety, which I will come to in a minute. On efficacy,

Ian F. Smith: 31% of patients in the vans are treated groups versus 23% of patients in the trade captor treated groups achieved sweat chloride levels below $30 million, leading to an odds ratio of 2.87 and a P value of 0.0001. This means about.

Three times greater likelihood in the odds of achieving sweat chloride less than 30 with vans a chapter versus try CAFTA. The results were even more pronounced in the ridge line study evaluating children ages six to 11. The primary endpoint in this single arm study was safety, which I will come to in a minute.

Ian F. Smith: On efficacy.

On efficacy, 95% of patients achieved sweat chloride below 60 millimole, the diagnostic threshold for cystic fibrosis. And more than half reached sweat chloride levels below the carrier level threshold of 30 millimoles. These sweat chloride results with the VANZA Triple are both impressive and important. Let me take a step back to frame the significance of these results. While CF is a systemic multi-organ disease, historically, the focus has been primarily on lung function as measured by ppFEV1. Given, it is the most visible symptom and typically the cause of death in CF patients. ppFEV1 is also the regulatory.

Ian F. Smith: 95% of patients achieved sweat chloride below 60, millimole, the diagnostic threshold for cystic fibrosis and more than half reached sweat chloride levels below the carrier level threshold of 30 Millimole. These.

Ian F. Smith: The sweat chloride results with the vans, a triple our both impressive and important let me take a step back to frame the significance of these results.

While CF is a systemic multi organ disease. Historically, the focus has been primarily on lung function as measured by P. P. F. E V. One given it is the most visible symptom and typically the cause of death in CF patients P. P. F. E V. One is also the regulatory.

ppFEV1 is also the regulatory-enabling endpoint. Given the strides we've made with TRIKAFTA, we believe we may have reached the maximum potential benefit in lung function from see FTR modulators, that's our objective with vans or capture moves beyond the focus on lung function to a broader more ambitious goal to improve seed. T R protein function as measured by lower sweat chloride levels and deliver even greater systemic benefit that try CAFTA.

ppFEV1 is also the regulatory-enabling endpoint.

Ian F. Smith: Neighboring endpoint given the strides we've made with truck CAFTA. We believe we may have reached the maximum potential benefit in lung function from see FTR modulators, that's our objective with vans or capture moves beyond the focus on lung function to a broader more ambitious goal to improve seed.

Given the strides we've made with TRIKAFTA, we believe we may have reached the maximum potential benefit in lung function from CFTR modulators. Thus, our objective with VANZACAFTOR moves beyond the focus on lung function to a broader, more ambitious goal to improve CFTR protein function as measured by lower sweat chloride levels and deliver even greater systemic benefit than TRIKAFTA. To be clear, the goal with the VANZA pivotal development program was to show the lung function benefit was non-inferior to TRIKAFTA and over and above that, to deliver additional benefit on sweat chloride, the direct marker of CFTR protein function. A note on CFTR protein --

Ian F. Smith: T R protein function as measured by lower sweat chloride levels and deliver even greater systemic benefit that try CAFTA.

Ian F. Smith: To be clear the goal with the vans. The pivotal development program was to show the lung function benefit was non inferior to try CAFTA and over and above that to deliver additional benefit on sweat chloride. The direct marker of see FTR protein function a note on CFT our protein.

A note on CFTR protein -- CFTR protein dysfunction is the underlying pathophysiology in CF. And while CF is often diagnosed by a genetic test at birth, it is confirmed via a sweat chloride test because it is the direct measure of CFTR protein dysfunction. Simply put, higher levels of sweat chloride is associated with more severe disease. Therefore, the ultimate goal is to restore CFTR protein function, as measured by sweat chloride, back to normal or as close to normal as possible so that there is no manifestation of disease. And more specifically, sweat chloride values below 60 millimoles are associated with improved outcomes, such as better and more stable lung function, fewer pulmonary exacerbations, better quality of life and improved survival. Vertex's ultimate treatment goal is to restore sweat chloride levels to below 30, which is considered normal and are typical of CF carriers who do not have the disease. For instance, the parents of children with CF.

Ian F. Smith: C F T. Our protein dysfunction is the underlying pathophysiology in CF and while CF is often diagnosed by a genetic test that birth. It is confirmed we are sweat chloride test because it is the direct measure of CFT, our protein dysfunction simply put higher levels of sweat chloride associated with.

Ian F. Smith: More severe disease. Therefore, the ultimate goal is to restore C. F T. Our protein function as measured by sweat chloride back to normal or as close to normal as possible. So that there is no manifestation of disease and more specifically sweat chloride values below 60 mill.

And more specifically, sweat chloride values below 60 millimoles are associated with improved outcomes, such as better and more stable lung function, fewer pulmonary exacerbations, better quality of life and improved survival. Vertex's ultimate treatment goal is to restore sweat chloride levels to below 30, which is considered normal and are typical of CF carriers who do not have the disease. For instance, the parents of children with CF.

Ian F. Smith: The molds are associated with improved outcomes, such as better and more stable lung function fewer pulmonary exacerbations better quality of life and improve survival vertex is ultimate treatment goal is to restore sweat chloride levels to below 30, which is considered normal and our typical of <unk>.

Vertex's ultimate treatment goal is to restore sweat chloride levels to below 30, which is considered normal and are typical of CF carriers who do not have the disease. For instance, the parents of children with CF. Thus, our goal in designing the VANZACAFTOR Triple therapy studies was to test if even more patients treated with VANZA could achieve those sweat chloride thresholds of less than 60 and less than 30 than those treated with TRIKAFTA. Switching to safety, the VANZA Triple was generally safe and well-tolerated in all three studies. The adverse events seen in the VANZA Triple pivotal development program are consistent with the underlying disease and with the incidents and nature of adverse events, we have seen with previous CFTR modulators. As a reminder, and to round out the profile of the VANZACAFTOR Triple, this therapy offers the convenience of once-daily dosing for patients and a substantially lower royalty burden.

F carriers, who do not have the disease for instance, the parents of children with CF.

Ian F. Smith: Our goal in designing the vans the captor Triple therapy studies was to test if even more patients treated with banzer could achieve those sweat chloride thresholds of less than 60 and less than 30 than those treated with tri CAFTA switching to safety the vans a triple was generally say. And well tolerated in all three studies the adverse events seen in the vans are triple pivotal development program are consistent with the underlying disease and with the incidents and nature of adverse events, we have seen with previous C. F. T. R. Modulators as a reminder, and to round out the profile of the vans a cap. Triple This therapy offers the convenience of once daily dosing for patients and a substantially lower royalty burden.

Switching to safety, the VANZA Triple was generally safe and well-tolerated in all three studies. The adverse events seen in the VANZA Triple pivotal development program are consistent with the underlying disease and with the incidents and nature of adverse events, we have seen with previous CFTR modulators. As a reminder, and to round out the profile of the VANZACAFTOR Triple, this therapy offers the convenience of once-daily dosing for patients and a substantially lower royalty burden.

Ian F. Smith: And well tolerated in all three studies the adverse events seen in the vans are triple pivotal development program are consistent with the underlying disease and with the incidents and nature of adverse events, we have seen with previous C. F. T. R. Modulators as a reminder, and to round out the profile of the vans a cap.

Ian F. Smith: Triple This therapy offers the convenience of once daily dosing for patients and a substantially lower royalty burden.

Ian F. Smith: In summary, we set a goal to establish a new and higher bar in the treatment of CF with CFTR modulators and with these Phase III VANZA Triple results, we have the first evidence that we have done so. And with these results, we now know that the VANZA Triple has indeed surpassed the very high bar set by TRIKAFTA in people with CF, ages 6 and older. And by treating patients early with the VANZA Triple, we have the potential to possibly prevent systemic manifestations of CF in more people. These results also reaffirm our conviction that continued investment in scientific and serial innovation will allow us to complete our journey to transform CF by bringing all eligible CF patients down to carrier levels of sweat chloride, where there are no manifestations of disease.

Ian F. Smith: Bar set by try CAFTA in people with CF ages, six and older.

Ian F. Smith: And by treating patients early with the vans, a triple we have the potential to possibly prevent systemic manifestations of CF in more people.

Ian F. Smith: These results also reaffirm our conviction that continued investment in scientific and serial innovation will allow us to complete our journey to transform CF by bringing all eligible CF patients down to carrier levels of sweat chloride, where there are no manifestations of disease.

I want to acknowledge the CF patients in our clinical trials, who put their trust in us. As well as the Vertex San Diego team and the CF R&D teams, some of whom have worked on CF for more than 20 years, to deliver yet another potentially transformative medicine. We're working rapidly to compile the regulatory submissions and anticipate filing in both the US and Europe, for patients ages 6 and older, by the middle of 2024. We will be using one of our priority review vouchers, entitling us to designate the VANZA NDA for priority review, which provides an expedited six-month review versus a standard 10-month review timeline. I'll close on CF with VX 522 are see FTR mrna therapy in development with our partners that Madonna for the more than 5000, and CF patients, who do not make any C. F T. Our protein and therefore cannot benefit from CF GR modulators lately.

Ian F. Smith: Troy submissions and anticipate filing in both the U S and Europe for patients ages, six and older by the middle of 'twenty 'twenty four we will be using one of our priority review vouchers entitling us to designate the vans a N D E for priority review, which provides an expedited six month review.

Ian F. Smith: <unk> is a standard 10 month review timeline I'll close on CF with VX 522 are see FTR mrna therapy in development with our partners that Madonna for the more than 5000, and CF patients, who do not make any C. F T. Our protein and therefore cannot benefit from CF GR modulators lately.

I'll close on CF with VX-522, our CFTR mRNA therapy in development with our partners at Moderna, for the more than 5,000 CF patients who do not make any CFTR protein and therefore, cannot benefit from CFTR modulators. Late last year, we completed enrollment and dosing in the single-ascending dose portion of our study for VX-522 and initiated the multiple-ascending dose portion of the study. This study continues to screen, enroll and dose patients and we expect data late this year or early next.

Ian F. Smith: Last year, we completed enrollment and dosing in the single sending dose portion of our study for VX 522, and initiated the multiple ascending dose portion of the study. This study continues to screen and Roland dose patients and we expect data late this year or early next.

Ian F. Smith: Turning now to CASHGEVY, a precise durable CRISPR/CAS9 gene-edited therapy that delivers a potential one-time functional cure for patients with sickle cell disease and transfusion-dependent beta thalassemia. CASHGEVY represents an enormous advancement for the estimated 35,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia across the US and Europe, as well as thousands of patients in other regions, such as the Kingdom of Saudi Arabia and Bahrain. CASHGEVY represents a significant commercial opportunity as well. And Stuart will discuss the strong start to the launch, following

Turning now to CASHGEVY, a precise durable CRISPR/Cas9 gene-edited therapy that delivers a potential one-time functional cure for patients with sickle cell disease and transfusion-dependent beta thalassemia. CASHGEVY represents an enormous advancement for the estimated 35,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia across the US and Europe, as well as thousands of patients in other regions, such as the Kingdom of Saudi Arabia and Bahrain. CASHGEVY represents a significant commercial opportunity as well.

Turning now to CASGEVY, a precise durable CRISPR/Cas9 gene-edited therapy that delivers a potential one-time functional cure for patients with sickle cell disease and transfusion-dependent beta thalassemia. CASGEVY represents an enormous advancement for the estimated 35,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia across the US and Europe, as well as thousands of patients in other regions, such as the Kingdom of Saudi Arabia and Bahrain.

Ian F. Smith: Cell disease, and transfusion dependent beta thalassemia across the U S and Europe as well as thousands of patients in other regions such as the Kingdom of Saudi Arabia, and Bahrain catch every represents a significant commercial opportunity as well and Stuart will discuss the strong start to the launch following.

CASGEVY represents a significant commercial opportunity as well. And Stuart will discuss the strong start to the launch, following the rapid approvals in multiple countries. While these launches are underway, we are awaiting approval in the EU, where CASGEVY has received CHMP Positive Opinion for both sickle cell disease and beta thalassemia. CASGEVY's also under review in Switzerland and we anticipate filing in Canada this quarter.

And Stuart will discuss the strong start to the launch, following the rapid approvals in multiple countries. While these launches are underway, we are awaiting approval in the EU, where CASHGEVY has received CHMP Positive Opinion for both sickle cell disease and beta thalassemia. CASHGEVY's also under review in Switzerland and we anticipate filing in Canada this quarter.

Ian F. Smith: The rapid approvals in multiple countries. While these launches are underway. We are awaiting approval in the EU, where cash Chevy has received C. H M. P positive opinion for both sickle cell disease and beta thalassemia cashed Gebbie's also under review in Switzerland, and we anticipate filing in Canada.

This quarter.

Ian F. Smith: Lastly on CASGEVY -- recognizing the importance of treating patients with sickle cell disease and beta thalassemia early in life to minimize organ damage and other complications of the disease, we are conducting studies in both sickle cell disease and beta thalassemia to expand the label to younger age groups. To that end, we recently completed enrollment in our two global Phase III studies in patients 5 to 11 years of age and dosing in these studies is underway.

Ian F. Smith: We completed enrollment in our two global Phase III studies in patients five to 11 years of age and dosing in these studies is underway move.

Ian F. Smith: Moving to the pain program and VX-548, our novel highly selective NaV1.8 pain signal inhibitor. With VX-548, we finally have the possibility of a medicine that has the compelling combination of both strong efficacy and strong safety that can be used for multiple moderate to severe pain types across multiple settings of care. Last week, we detailed the positive results from the three Phase III trials that comprise our pivotal program for VX-548 in acute pain, including randomized placebo-controlled trials in two different pain models -- abdominoplasty, a soft tissue pain model and bunionectomy, a hard tissue pain model. And a single arm safety and effectiveness trial in a broad range of surgical and non-surgical pain conditions. Both the abdominoplasty and bunionectomy RCT's met the primary endpoint with statistically significant improvement in pain, compared to placebo on the primary endpoint of SPID48.

Moving to the pain program and VX-548, our novel highly selective NaV1.8 pain signal inhibitor. With VX-548, we finally have the possibility of a medicine that has the compelling combination of both strong efficacy and strong safety that can be used for multiple moderate to severe pain types across multiple settings of care. Last week, we detailed the positive results from the three Phase III trials that comprise our pivotal program for VX-548 in acute pain, including randomized placebo-controlled trials in two different pain models -- abdominoplasty, a soft tissue pain model and bunionectomy, a hard tissue pain model. And a single arm safety and effectiveness trial in a broad range of surgical and non-surgical pain conditions.

Ian F. Smith: With VX 548, we finally have the possibility of a medicine that has the compelling combination of both strong efficacy and strong safety that can be used for multiple moderate to severe pain types across multiple settings of care.

Ian F. Smith: Last week, we detailed the positive results from the three phase III trials that comprise our pivotal program for VX five four rate in acute pain, including randomized placebo controlled trials in two different pain models, abdominoplasty or soft tissue pain model and Bunionectomy, a hard tissue pain model and a single arm.

Safety and effectiveness trial in a broad range of surgical and nonsurgical pain conditions, both the Abdominoplasty and Bunionectomy Rct's met the primary endpoint with statistically significant improvement in pain compared to placebo on the primary endpoint of speed 48.

Both the abdominoplasty and bunionectomy RCT's met the primary endpoint with statistically significant improvement in pain, compared to placebo on the primary endpoint of SPID48. The SPID48 is derived from a change in the numeric pain rating scale or NPRS. Practicing physicians tell us, that in addition to SPID48, they focus on this reduction in the NPRS from baseline and this change in baseline in NPRS score is also how clinical meaningfulness is assessed in the field. In acute post-operative pain studies, clinical meaningfulness is defined by at least a two-point change in NPRS from baseline or at least a 30% reduction in NPRS from baseline.

Ian F. Smith: The split 48 is derived from a change in the numeric pain rating scale or N. P. R. S.

Ian F. Smith: Practicing physicians tell us that in addition to split 48, they focus on this reduction in the N P. R. S from baseline.

Ian F. Smith: And this change in baseline in N. P. R. S score is also how clinical meaningfulness is assessed in the field.

Ian F. Smith: In acute post-operative pain studies, clinical meaningfulness is defined by at least a two-point change in NPRS from baseline or at least a 30% reduction in NPRS from baseline. In that context, both RCT's demonstrated that treatment with VX-548 led to rapid, clinically meaningful reductions on the NPRS with more than three points of pain reduction or roughly a 50% reduction from baseline in the VX-548 arms. The single arm safety and effectiveness trial was conducted in a broad range of surgical and non-surgical pain conditions and supported longer term safety and effectiveness. VX-548 was safe and well-tolerated across all three studies, including multiple acute pain types and settings.

In acute post-operative pain studies, clinical meaningfulness is defined by at least a two-point change in NPRS from baseline or at least a 30% reduction in NPRS from baseline.

In that context, both RCT's demonstrated that treatment with VX-548 led to rapid, clinically meaningful reductions on the NPRS with more than three points of pain reduction or roughly a 50% reduction from baseline in the VX-548 arms. The single arm safety and effectiveness trial was conducted in a broad range of surgical and non-surgical pain conditions and supported longer term safety and effectiveness. VX-548 was safe and well-tolerated across all three studies, including multiple acute pain types and settings.

Ian F. Smith: Led to rapid clinically meaningful reductions on the N. P. R S with more than three points of pain reduction or roughly a 50% reduction from baseline in the VX five four rate arms.

Ian F. Smith: The single arm safety and effectiveness trial was conducted in a broad range of surgical and nonsurgical pain conditions and supported longer term safety and effectiveness.

Ian F. Smith: VX 548 was safe and well tolerated across all three studies, including multiple acute pain types and settings.

Ian F. Smith: Of importance with respect to safety in the to our C. Ts the incidents of adverse events in the VX 548 arms was lower than placebo and uncommon and noteworthy finding. We believe the results of this comprehensive phase III program support a broad moderate to severe acute pain label and if approved should enable prescribing and usage across multiple care settings. 548 has already secured fast track and breakthrough designation and we are working with urgency to file the NDA by mid 'twenty 'twenty four moving now to neuropathic pain two months ago. We also reported positive results from our phase two study of VX five four rate in diabetic peripheral neuropathy.

Of importance, with respect to safety in the two RCTs, the incidents of adverse events in the VX-548 arms was lower than placebo and uncommon and noteworthy-finding. We believe the results of this comprehensive Phase III program support a broad moderate to severe acute pain label and if approved, should enable prescribing and usage across multiple care settings. VX-548 has already secured fast track and breakthrough designations and we are working with urgency to file the NDA by mid 2024. Moving now to neuropathic pain. Two months ago.

Ian F. Smith: We believe the results of this comprehensive phase III program support a broad moderate to severe acute pain label and if approved should enable prescribing and usage across multiple care settings.

Ian F. Smith: 548 has already secured fast track and breakthrough designation and we are working with urgency to file the NDA by mid 'twenty 'twenty four moving now to neuropathic pain two months ago. We also reported positive results from our phase two study of VX five four rate in diabetic peripheral neuropathy.

Moving now to neuropathic pain. Two months ago, we also reported positive results from our Phase II study of VX-548 in diabetic peripheral neuropathy -- one type of peripheral neuropathic pain and another area of high unmet need. We look forward to our end of Phase II meeting with the FDA towards the end of this quarter and starting our Phase III program thereafter. We also continued to enroll and dose our second Phase II neuropathic pain study of VX-548 in lumbosacral radiculopathy or LSR.

We also reported positive results from our phase two study of VX five four rate in diabetic peripheral neuropathy. With the one type of peripheral neuropathic pain and another area of high unmet need we look forward to our end of phase two meeting with the FDA towards the end of this quarter and starting our phase III program. Thereafter, we also continued to enroll and dose our second phase III neuropathy.

Ian F. Smith: With the one type of peripheral neuropathic pain and another area of high unmet need we look forward to our end of phase two meeting with the FDA towards the end of this quarter and starting our phase III program. Thereafter, we also continued to enroll and dose our second phase III neuropathy.

Ian F. Smith: The pain study of VX 548 in lumbosacral, Radiculopathy or L. S. Saar.

Ultimately, we seek a broad neuropathic pain label and believe by studying two of the largest pain segments, DPN and LSR, which together represent more than 60% of all peripheral neuropathic pain -- we have a pathway to that broad indication. Just as we transformed the treatment of CF, we believe we have the potential to transform the treatment of pain -- both acute and neuropathic -- based on the compelling and consistent results we have seen with VX-548. We now have results in hand from the Phase III program in acute pain as well as the phase two results in DPN. We are underway with the Phase II study in LSR and we are continuing to execute our portfolio approach of serial innovation. We are well on our way to helping address the unmet need of 90 million patients suffering with pain.

Ian F. Smith: Transformed the treatment of CF, we believe we have the potential to transform the treatment of pain, both acute and neuropathic based on the compelling and consistent results. We have seen with VX 548, we now have results in hand from the phase III program in acute pain as well.

We now have results in hand from the Phase III program in acute pain as well as the phase two results in DPN. We are underway with the Phase II study in LSR and we are continuing to execute our portfolio approach of serial innovation. We are well on our way to helping address the unmet need of 90 million patients suffering with pain.

Ian F. Smith: As the phase two results in D. P N.

Ian F. Smith: We are underway with the phase two study in <unk> and we are continuing to execute our portfolio approach of serial innovation. We are well on our way to helping address the unmet need of 90 million patients suffering with pain.

Ian F. Smith: We are well on our way to helping address the unmet need of 90 million patients suffering with pain.

Ian F. Smith: With that, I'll now turn it over to Stuart.

Thanks, Reshma. With the recent approvals of CASHGEVY in sickle cell disease and transfusion-dependent thalassemia in multiple countries and the recent positive results in our pivotal trials for VX-548 in acute pain and for the VANZACAFTOR Triple combination in CF, we are well and truly entering a new era of commercial diversification. As Reshma noted, we delivered strong 4th quarter and full year commercial results in CF, as we continue to grow the number of eligible patients receiving our CFTR modulators. 4th quarter US growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 years old, following the approval for these patients in April. Outside the US,

Stuart Arbuckle: Thanks, Reshma. With the recent approvals of CASGEVY in sickle cell disease and transfusion-dependent thalassemia in multiple countries and the recent positive results in our pivotal trials for VX-548 in acute pain and for the VANZACAFTOR Triple combination in CF, we are well and truly entering a new era of commercial diversification. As Reshma noted, we delivered strong 4th quarter and full year commercial results in CF, as we continue to grow the number of eligible patients receiving our CFTR modulators. 4th quarter US growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 years old, following the approval for these patients in April.

As Reshma noted, we delivered strong 4th quarter and full year commercial results in CF, as we continue to grow the number of eligible patients receiving our CFTR modulators. 4th quarter US growth was driven by continued strong performance of TRIKAFTA, including in patients ages 2 to 5 years old, following the approval for these patients in April.

<unk> strong fourth quarter and full year commercial results and see us as we continue to grow the number of eligible patients receiving our C. F T. Our modulators fourth quarter U S growth was driven by continued strong performance of Tri CAFTA, including in patients ages two to five years old following the approval for these patients in April outside the U S.

Outside the US, we saw continued growth from both label expansions and new reimbursement agreements. In the near-term, we will continue to focus on reaching more eligible patients, including younger age groups, which will provide revenue growth. And then we expect to drive further growth with the VANZACAFTOR Triple combination. Given the positive Phase III data we released today that demonstrates a strong benefit-risk profile and the ability to deliver greater restoration of CFTR function than even TRIKAFTA, we believe the VANZACAFTOR Triple combination will be widely welcomed by the CF community, both as a new treatment option for the greater than 6,000 patients who have discontinued one of our current CFTR modulators and as an opportunity for TRIKAFTA patients to achieve even greater levels of CFTR function.

Ian F. Smith: We saw continued growth from both label expansions and new reimbursement agreements in the near term, we will continue to focus on reaching more eligible patients, including younger age groups, which will provide revenue growth and then we expect to drive further growth with the Venza CAFTA Triple combination given the positive phase three data, we released today that demonstrates a.

Given the positive Phase III data we released today that demonstrates a strong benefit-risk profile and the ability to deliver greater restoration of CFTR function than even TRIKAFTA, we believe the VANZACAFTOR Triple combination will be widely welcomed by the CF community, both as a new treatment option for the greater than 6,000 patients who have discontinued one of our current CFTR modulators and as an opportunity for TRIKAFTA patients to achieve even greater levels of CFTR function.

Ian F. Smith: Strong benefit risk profile and the ability to deliver greater restoration of C. F. T. A function then even try CAFTA. We believe the vans are capped a triple combination will be widely welcomed by the CF community, both as a new treatment option for the greater than 6000 patients who have discontinued one of our currency FTR modulators and as an opportunity for <unk>.

Half the patients to achieve even greater levels of C. F. T. R function longer term, we see additional growth from our mrna program VX 522 that we are developing in partnership with Madonna for the more than 5000, and CF patients with mutations that do not respond to C. F. T. Our modulators. In addition, we recently updated our estimate of the number.

Half the patients to achieve even greater levels of C. F. T. R function

Longer term, we see additional growth from our mRNA program, VX-522, that we are developing in partnership with Moderna for the more than 5,000 CF patients with mutations that do not respond to CFTR modulators. In addition, we recently updated our estimate of the number of people living with CF in North America, Europe and Australia, to 92,000 from the previous estimate of 88,000. This increase is in large part due to patients living longer as a result of improvements in CF care, including the advent of CFTR modulators. We expect this trend to continue based on the real world evidence we have generated on the clinical benefits of CFTR modulators. And this will also drive long-term growth. Now, turning to CASHGEVY and our launches in sickle cell disease and beta thalassemia.

Longer term, we see additional growth from our mRNA program, VX-522, that we are developing in partnership with Moderna for the more than 5,000 CF patients with mutations that do not respond to CFTR modulators. In addition, we recently updated our estimate of the number of people living with CF in North America, Europe and Australia to 92,000 from the previous estimate of 88,000. This increase is in large part due to patients living longer as a result of improvements in CF care, including the advent of CFTR modulators. We expect this trend to continue based on the real world evidence we have generated on the clinical benefits of CFTR modulators. And this will also drive long-term growth.

If people living with CF in North America, Europe, and Australia to 92000 from the previous estimate of 88000. This increases in large part due to patients living longer as a result of improvements in CF care, including the advent of C. F. T. Our modulators. We expect this trend to continue based on the real world evidence we have gen.

<unk> on the clinical benefits of CFT, our modulators and this will also drive long term growth now turning to cash JV and our launches in sickle cell disease and beta thalassemia.

Now, turning to CASGEVY and our launches in sickle cell disease and beta thalassemia. Enthusiasm from patients, physicians and payers is very high around the globe and we are focused on translating the scientific and medical innovation that CASGEVY represents into transformative patient benefit in the real world. In countries where CASGEVY has been approved, our sales reimbursement and access teams, as well as patient engagement teams, have hit the ground running. Let me provide some insights on the early days of the launch.

Ian F. Smith: Enthusiasm from patients physicians and payers is very high around the globe and we are focused on translating the scientific and medical innovation that cash do you have any represents.

Two transformative patient benefit in the real world in countries, where cash JV has been approved our sales reimbursement and access teams as well as patient engagement teams have hit the ground running let me provide some insights on the early days of the launch.

Ian F. Smith: Starting with physicians. There is tremendous interest in CASHGEVY and what it can do for their patients and we see the impact of that in the rapid activation of authorized treatment centers. Less than two months post-approval, we already have twelve ATCs in the US, three in the EU and one in the Kingdom of Saudi Arabia, all ready to receive patients. Reaction from payers has also been very positive. In the US, across commercial and government payers, all eligible CASHGEVY patients have case-by-case coverage through single case agreements. We continue to see excellent progress from payers on the development of their formal medical policies and reimbursement pathways. We have a contract in place with Synergy for up to a 100 million lives and are actively engaged with other commercial payers to finalize medical policies, which would bring the total percentage of covered lives to over 80%.

Starting with physicians. There is tremendous interest in CASGEVY and what it can do for their patients and we see the impact of that in the rapid activation of authorized treatment centers. Less than two months post-approval, we already have twelve ATCs in the US, three in the EU and one in the Kingdom of Saudi Arabia, all ready to receive patients. Reaction from payers has also been very positive.

Ian F. Smith: There is tremendous interest in cash JV and what it can do for their patients and we see the impact of that in the rapid activation of authorized treatment centers.

Ian F. Smith: Less than two months post approval, we already have 12 86 in the U S. Three in the EU and one in the Kingdom of Saudi Arabia already to receive patients.

Ian F. Smith: Reaction from payers has also been very positive.

Ian F. Smith: In the U S across commercial and government payers all eligible cast JV patients have case by case coverage through single case agreements. We continue to see excellent progress from payers on the development of their formal medical policies and reimbursement pathways. We have a contract in place with synergy for up to a 100 million lives and are actively engaged.

In the US, across commercial and government payers, all eligible CASGEVY patients have case-by-case coverage through single case agreements. We continue to see excellent progress from payers on the development of their formal medical policies and reimbursement pathways. We have a contract in place with Synergy for up to a 100 million lives and are actively engaged with other commercial payers to finalize medical policies, which would bring the total percentage of covered lives to over 80%.

Ian F. Smith: Aged with other commercial payers to finalize medical policies, which would bring the total percentage of covered lives to over 80%.

Ian F. Smith: In the government sector, Medicaid state agencies, representing over 60% of sickle cell disease lives, have established reimbursement pathways for CASHGEVY, with an additional 25% of Medicaid sickle cell disease lives in states actively progressing their reimbursement methodologies. In addition, we were pleased to have received the January approval in the US for CASHGEVY for transfusion-dependent thalassemia patients two and a half months early and are working to achieve a similarly fast trajectory for gaining reimbursement and access for these patients. Last week, there was an important update by the Biden administration on the CMMI Cell and Gene Therapy Access Model that

In the government sector, Medicaid state agencies, representing over 60% of sickle cell disease lives, have established reimbursement pathways for CASGEVY, with an additional 25% of Medicaid sickle cell disease lives in states actively progressing their reimbursement methodologies. In addition, we were pleased to have received the January approval in the US for CASGEVY for transfusion-dependent thalassemia patients two and a half months early and are working to achieve a similarly fast trajectory for gaining reimbursement and access for these patients.

Ian F. Smith: In the U S for cash JV for transfusion dependent thalassemia patients two and a half months early and are working to achieve a similarly fast trajectory for gaining reimbursement and access for these patients last week. There was an important update by the Barton administration on the CMI cell and gene therapy access demonstration model that.

Last week, there was an important update by the Biden administration on the CMMI Cell and Gene Therapy Access Model that was originally announced in February of 2023 and was recently accelerated for implementation from 2026 to 2025. We believe the CMMI CGT Access Model could be an important additional part of access and we now have greater clarity on the scope and process to be employed in the model. The model is intended to provide a comprehensive strategy to address barriers to equitable access to cell and gene therapies for Medicaid beneficiaries, as well as the long-standing inequities of care in the sickle cell disease community. Last week's update also confirmed additional federal funding to support access and included a defined scope of manufacturer-provided fertility support in the model, in recognition that for patients choosing to embark on the treatment journey, the cost of fertility preservation are a barrier to access. In the meantime, we continue to actively engage with state Medicaid agencies to finalize medical policies for CASHGEVY, even in advance of the CGT Access Model, to ensure patient access without delay.

Ian F. Smith: Was originally announced in February of 2023 and was recently accelerated for implementation from 2026 to 2025, we believe the CMI C. G. T access model could be an important additional part of access and we now have greater clarity on the scope and process to be employed in the model. The model is intended.

Ian F. Smith: To provide a comprehensive strategy to address barriers to equitable access to cell and gene therapies for Medicaid beneficiaries as well as the long standing in equities of care in the sickle cell disease community last week's update also confirmed additional federal funding to support access and included a defined scope of manufacturer provided fertility.

Last week's update also confirmed additional federal funding to support access and included a defined scope of manufacturer-provided fertility support in the model, in recognition that for patients choosing to embark on the treatment journey, the cost of fertility preservation are a barrier to access. In the meantime, we continue to actively engage with state Medicaid agencies to finalize medical policies for CASGEVY, even in advance of the CGT Access Model, to ensure patient access without delay.

Ian F. Smith: Reported the model in recognition that for patients choosing to embark on the treatment journey. The cost of fertility preservation are a barrier to access in the meantime, we continue to actively engage with state Medicaid agencies to finalize medical policies for cash JV, even in advance of the CGT access model to ensure patient access without.

Ian F. Smith: Delay.

Ian F. Smith: Outside the US, we are pleased the French National Authority for Health has approved our request for the implementation of an Early Access Program, or EAP, for TDT patients ages 12 to 35 years. We are delighted to have secured a path to access and payment in France ahead of a national reimbursement agreement and are also in an EAP review process for sickle cell disease patients. In the UK, CASGEVY will be reviewed by the highly specialized Technology Committee in February and we are advancing our reimbursement discussions in other European countries as well.

Or assess for sickle cell disease patients in the U K cash Jerry will be reviewed by the highly specialized technology Committee in February and we are advancing our reimbursement discussions in other European countries as well.

Ian F. Smith: We also see strong progress in the Middle East, which is especially important for CASHGEVY given the high prevalence of these diseases in the region and the government's clear focus on elevating the health of their citizens. We are working with local health care authorities in the Kingdom of Saudi Arabia and Bahrain to refine our estimates of the exact number of eligible patients but there are thousands of patients we could serve and we are focused on securing access and reimbursement for them. We have established a local presence in the region, have already activated our first ATC and are working with local healthcare professionals to expand the number of ATCs and establish the required infrastructure to meet patient demand. As we've previously outlined, the CASHGEVY patient journey can be broken down into three key phases, each of which can take several months. Pre-treatment, cell collection and manufacturing and then infusion of the edited cells.

We also see strong progress in the Middle East, which is especially important for CASGEVY given the high prevalence of these diseases in the region and the government's clear focus on elevating the health of their citizens. We are working with local health care authorities in the Kingdom of Saudi Arabia and Bahrain to refine our estimates of the exact number of eligible patients but there are thousands of patients we could serve and we are focused on securing access and reimbursement for them.

Ian F. Smith: We are working with local health care authorities in the Kingdom of Saudi Arabia, and Bahrain to refine our estimates of the exact number of eligible patients, but there are thousands of patients we could serve and we are focused on securing access and reimbursement for them. We have established a local presence in the region have already activated our first a T C and are working with local.

We have established a local presence in the region, have already activated our first ATC and are working with local healthcare professionals to expand the number of ATCs and establish the required infrastructure to meet patient demand. As we've previously outlined, the CASGEVY patient journey can be broken down into three key phases, each of which can take several months. Pre-treatment, cell collection and manufacturing and then infusion of the edited cells.

Ian F. Smith: Health care professionals to expand the number of E T CS and established the required infrastructure to meet patient demand as we've previously outlined the cached every patient journey can be broken down into three key phases, each of which can take several months pretreatment cell collection in manufacturing and then infusion of the edited cells.

Ian F. Smith: We are pleased with the early days of what will be a foundational year for CASHGEVY as we work to deliver transformative patient outcomes with the possibility of a lifetime of benefit. We look forward to updating you on the CASHGEVY launch over the course of this year. To help track our progress, our expectation is to provide quarterly updates on the number of activated ATCs as well as the number of patients in the cell collection phase. ATCs have begun assessing their patients for the ability to be treated with CASHGEVY and we expect that the first commercial patients will start the journey in the coming weeks. Shifting now to VX five.

We are pleased with the early days of what will be a foundational year for CASGEVY as we work to deliver transformative patient outcomes with the possibility of a lifetime of benefit. We look forward to updating you on the CASGEVY launch over the course of this year. To help track our progress, our expectation is to provide quarterly updates on the number of activated ATCs as well as the number of patients in the cell collection phase. ATCs have begun assessing their patients for the ability to be treated with CASGEVY and we expect that the first commercial patients will start the journey in the coming weeks.

Ian F. Smith: To help track our progress our expectation is to provide quarterly updates on the number of activated T. CS as well as a number of patients in the cell collection phase a T. CS have begun assessing their patients for the ability to be treated with cash jiffy and we expect that the first commercial patients will start the journey in the coming weeks shifting now to VX five.

Shifting now to VX-548. We are very excited about the potential for this highly selective NaV1.8 inhibitor to provide a transformative treatment option for the millions of patients suffering from acute and peripheral neuropathic pain. This quarter, I'll limit my comments to acute pain. As we discussed last week when we shared the results from the pivotal program, we are very excited about VX-548's compelling combination of efficacy and safety; and the demonstration that it can be used for moderate to severe pain across a range of pain conditions, both surgical and non-surgical, and across a range of settings. If approved, VX-548 will be the first of a new class of medicines that inhibit the pain signal and represent the first new class of medicines for acute pain in over 20 years.

Ian F. Smith: Alright.

Ian F. Smith: We are very excited about the potential for this highly selective NAV one eight inhibitor to provide a transformative treatment option for the millions of patients suffering from acute and peripheral neuropathic pain. This quarter I'll limit my comments to acute pain as we discussed last week when we shared the results from the pivotal program. We are very excited about VX five.

Ian F. Smith: For its compelling combination of efficacy and safety and the demonstration that it can be used for moderate to severe pain across a range of pain conditions, both surgical and nonsurgical and across a range of settings. If approved VX 548 will be the first of a new class of medicines that inhibit the pain signal and represent.

If approved, VX-548 will be the first of a new class of medicines that inhibit the pain signal and represent the first new class of medicines for acute pain in over 20 years. The reason we're so excited about the potential for VX-548 to positively impact patient care is because we estimate approximately 80 million patients are prescribed medicine for moderate to severe acute pain every year in the US, representing over 1 billion calendar days of treatment. Given this massive patient population, acute pain is a multi-billion dollar market today, despite the fact that essentially all prescriptions are generic. We also see upside to this market opportunity given the significant unmet need that stems from the sub-optimal benefit/risk profiles of existing agents, such as the limited efficacy but acceptable side effects of NSAIDs or the adverse effects and addiction potential of opioids, all of which leads to sub-optimal pain management.

The first new class of medicines for acute pain in over 20 years.

Speaker Change: The reason, we're so excited about the potential for VX 548 to positively impact patient care is because we estimate approximately 80 million patients are prescribed medicine for moderate to severe acute pain every year in the U S representing over 1 billion calendar days of treatment given this massive patient population acute pain is a multibillion. Dollar market today, despite the fact that essentially all prescriptions are generic. We also see upside to this market opportunity given the significant unmet need that stems from the suboptimal benefit risk profiles of existing agents. Such as the limited efficacy, but acceptable side effects of nsaids or the adverse effects and addiction potential of opioids, all of which leads to suboptimal pain management.

Speaker Change: Dollar market today, despite the fact that essentially all prescriptions are generic.

Speaker Change: We also see upside to this market opportunity given the significant unmet need that stems from the suboptimal benefit risk profiles of existing agents.

We also see upside to this market opportunity given the significant unmet need that stems from the sub-optimal benefit/risk profiles of existing agents, such as the limited efficacy but acceptable side effects of NSAIDs or the adverse effects and addiction potential of opioids, all of which leads to sub-optimal pain management. What physicians and patients seek is a medicine that combines effective relief of moderate to severe pain, with a clear safety and tolerability profile. And VX-548 delivers on that profile.

Speaker Change: Such as the limited efficacy, but acceptable side effects of nsaids or the adverse effects and addiction potential of opioids, all of which leads to suboptimal pain management.

Speaker Change: What physicians and patients seek is a medicine that combines effective relief of moderate to severe pain with a clear safety and tolerability profile and VX 548 delivers on that profile.

Speaker Change: We've previously shared our go-to-market strategy and we are now actively recruiting our field force in anticipation of our regulatory filing and approval. The commercial team will focus on the roughly 2,000 hospitals and institutions, where a majority of acute pain patients are seen and prescriptions are written. We continue to see a multi-billion dollar opportunity for VX-548 in acute pain alone. The well-known risks of opioids have led to widespread restrictions and limitations on their use over the years. Increasingly, we are seeing a paradigm shift in policy initiatives across various stakeholders to encourage consideration and use of non-opioid alternatives and to remove financial barriers to choosing a branded non-opioid. As an example, late last month, Congress introduced the bipartisan alternatives to Prevent Addiction in the Nation Act or the Alternatives to PAIN Act.

We've previously shared our go-to-market strategy and we are now actively recruiting our field force in anticipation of our regulatory filing and approval. The commercial team will focus on the roughly 2,000 hospitals and institutions, where a majority of acute pain patients are seen and prescriptions are written. We continue to see a multi-billion dollar opportunity for VX-548 in acute pain alone. The well-known risks of opioids have led to widespread restrictions and limitations on their use over the years.

Speaker Change: We continue to see a multibillion dollar opportunity for VX 548 in acute pain alone the well known risks of opioids have led to widespread restrictions and limitations on their use over the years increasingly we are seeing a paradigm shift in policy initiatives across various stakeholders to encourage consideration and use of nano.

Increasingly, we are seeing a paradigm shift in policy initiatives across various stakeholders to encourage consideration and use of non-opioid alternatives and to remove financial barriers to choosing a branded non-opioid. As an example, late last month, Congress introduced the bipartisan alternatives to Prevent Addiction in the Nation Act or the Alternatives to PAIN Act. If enacted, Medicare Part D plans would be required to set co-pays for non-opioids like VX-548, in line with co-pays for generic opioids, which are typically between $0 and $15. The bill would also prohibit Medicare Part D plans from requiring seniors to step through opioids first or requiring prior authorization for non-opioids. In addition, the NOPAIN Act or Non-Opioids Prevent Addiction in the Nation Act, which was enacted in late 2022, provides for an add-on payment for non-opioids in the outpatient and ambulatory surgery center settings and remains on track to go into effect in 2025.

Speaker Change: P alternatives and to remove financial barriers to choosing a branded non opioid as an example late last month Congress introduced the bipartisan alternatives to prevent addiction in the Nation Act all the alternatives to paint Act.

Speaker Change: If enacted Medicare part D plans would be required to set co pays for non opioids like VX five four right in line with co pays for generic opioids, which are typically between north and $15. The Bill would also prohibit Medicare part D plans from acquiring seniors to step through opioids first all requiring <unk>.

The bill would also prohibit Medicare Part D plans from requiring seniors to step through opioids first or requiring prior authorization for non-opioids. In addition, the NOPAIN Act or Non-Opioids Prevent Addiction in the Nation Act, which was enacted in late 2022, provides for an add-on payment for non-opioids in the outpatient and ambulatory surgery center settings and remains on track to go into effect in 2025.

Speaker Change: Higher authorization for non opioids. In addition, the no pain act or non opioids prevent addiction in the Nation Act, which was enacted in late 2022 provides for an add on payment for non opioids in the outpatient and ambulatory surgery center settings and remains on track to go into effect in 2025.

Speaker Change: And just recently, seven states -- Maine, Massachusetts, Missouri, Oklahoma, Tennessee, Washington and West Virginia, have pending legislation that would require education on non-opioid options and would remove financial barriers to patient access within state-based health insurance programs like Medicaid. We expect additional states to introduce similar legislation later this year. We believe that these advances in federal and state legislation represent further momentum in Congress and across the US to encourage adoption of and remove any financial barriers to using non-opioid therapies like VX-548.

Speaker Change: We expect additional states to introduce similar legislation later this year, we believe that these advances in federal and state legislation represent further momentum in Congress and across the U S to encourage adoption of and remove any financial barriers to using non opioid therapies like VX 548.

Speaker Change: In conclusion, it's an incredibly exciting time at Vertex. We continue to treat more CF patients around the world and with the VANZA Triple, now have visibility to provide an option for the patients who have discontinued CFTR modulators, as well as the possibility to bring even more patients below diagnostic levels and even to carrier levels of sweat chloride. We're entering a new era of commercial diversification with the launch of CASGEVY, the first-ever, gene-edited therapy that brings a potential functional cure to patients with sickle cell disease and beta thalassemia across multiple regions. And we are preparing for additional near-term launches with significant market potential, including VX-548 in acute pain.

Speaker Change: We're entering a new era of commercial diversification with the launch of cash Jerry the first ever gene edited therapy that brings a potential functional cure to patients with sickle cell disease and beta thalassemia across multiple regions and we are preparing for additional near term launches with significant market potential including VX 548.

Speaker Change: In acute pain.

Speaker Change: I'll now turn the call over to Charlie to review the financials.

Charles Wagner: Thanks, Stuart. Vertex's excellent results in the 4th quarter of 2023 demonstrate, once again, our consistent strong performance and attractive growth profile. 4th quarter 2023 revenue increased 9% year-over-year to $2.52 billion and was nicely balanced with revenue growth of 8% in the US and 12% outside the US. Full year revenue of $9.87 billion represents 11% growth versus 2022, our ninth consecutive year of at least double digit growth. Overall, the primary drivers of revenue growth in 2023 are in line with our expectations.

Charlie Wagner: Vertex has excellent results in the fourth quarter of 2023 demonstrate once again, our consistent strong performance and attractive growth profile fourth quarter 2023 revenue increased 9% year over year to 2.52 billion and was nicely balanced with revenue growth of 8% in the U S and 12% out.

Charlie Wagner: <unk> the U S full year revenue of 9.87 billion represents 11% growth versus 2022, our ninth consecutive year of at least double digit growth overall, the primary drivers of revenue growth in 'twenty twenty-three or in line with our expectations.

Charlie Wagner: 4th quarter 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $1 billion compared to $872 million in the 4th quarter of 2022. Included in Q4 '23 results are $18 million of acquired IP R&D charges, compared to $23 million of such charges in the 4th quarter of 2022. Note that with the approval of CASGEVY in the 4th quarter, costs for manufacturing capacity for CASGEVY are now being recorded in cost of goods sold rather than in R&D.

Charlie Wagner: Compared to 872 million in the fourth quarter of 2022.

Charlie Wagner: Included in Q4 'twenty three results are 18 million of acquired IP R&D charges compared to $23 million of such charges in the fourth quarter of 2022.

Charlie Wagner: Note that with the approval of cast JV in the fourth quarter costs for manufacturing capacity for cast JV are now being recorded in cost of goods sold rather than in R&D.

Charlie Wagner: Full year 2023 combined non-GAAP R&D, acquired IP, R&D and SG&A expenses were $4.24 billion compared to $3.07 billion in 2022. 4th quarter and full year operating expense growth was driven, as expected, by continued investment in research and our pipeline, as we have now advanced assets into the clinic in nine different disease areas. In the 4th quarter and throughout 2023, the most significant areas of increased investment versus prior year included the pivotal studies for VX-548 in acute pain and the VANZACAFTOR Triple in CF, the Phase 1/2 study for type one diabetes, as well as the build out of capabilities for both our expanding pipeline and our anticipated near-term commercial launches. In addition, approximately $400 million of the year-over-year increase in operating expenses was the result of increased AIP R&D costs from new business development. 4th quarter 2023 non-GAAP operating income was $1.15 billion, consistent with $1.15 billion in non-GAAP operating income in the 4th quarter of 2022. Full year 2023 non-GAAP operating income was $4.37 billion, compared to 4.79 billion in 2022. 4th quarter 2023 effective tax rate of 16.3% reflects an increase in our 2023 US R&D tax credits. This benefit lowered the Q4 rate and brought the full year 2023 effective tax rate to 19.4%, slightly below our guidance range of 20% to 21%. 4th quarter 2023 in non-GAAP earnings per share were $4.20, representing 12% growth compared to $3.76 in the 4th quarter of 2022. Full year 2023 non-GAAP earnings per share were $15.23, compared to $14.88 in 2022.

Full year 2023 combined non-GAAP R&D, acquired IP, R&D and SG&A expenses were $4.24 billion compared to $3.07 billion in 2022. 4th quarter and full year operating expense growth was driven, as expected, by continued investment in research and our pipeline, as we have now advanced assets into the clinic in nine different disease areas. In the 4th quarter and throughout 2023, the most significant areas of increased investment versus prior year included the pivotal studies for VX-548 in acute pain and the VANZACAFTOR Triple in CF, the Phase 1/2 study for type one diabetes, as well as the build out of capabilities for both our expanding pipeline and our anticipated near-term commercial launches.

Charlie Wagner: <unk> fourth quarter and full year operating expense growth was driven as expected by continued investment in research and our pipeline as we have now advanced assets into the clinic in nine different disease areas.

Charlie Wagner: In the fourth quarter and throughout 2023, the most significant areas of increased investment versus prior year included the pivotal studies for VX 548 in acute pain and the Venza captor triple in CF. The phase one two study for type one diabetes as well as the build out of capabilities for both our expanding pipeline and our anticipated near term.

Commercial launches in addition, approximately $400 million of the year over year increase in operating expenses was the result of increased AIP R&D costs from new business development fourth quarter 2023, non-GAAP operating income was 1.15 billion consistent with 1.15 billion and non-GAAP operating income.

In addition, approximately $400 million of the year-over-year increase in operating expenses was the result of increased AIP R&D costs from new business development. 4th quarter 2023 non-GAAP operating income was $1.15 billion, consistent with $1.15 billion in non-GAAP operating income in the 4th quarter of 2022. Full year 2023 non-GAAP operating income was $4.37 billion, compared to 4.79 billion in 2022. 4th quarter 2023 effective tax rate of 16.3% reflects an increase in our 2023 US R&D tax credits. This benefit lowered the Q4 rate and brought the full year 2023 effective tax rate to 19.4%, slightly below our guidance range of 20% to 21%. 4th quarter 2023 in non-GAAP earnings per share were $4.20, representing 12% growth compared to $3.76 in the 4th quarter of 2022. Full year 2023 non-GAAP earnings per share were $15.23, compared to $14.88 in 2022.

Charlie Wagner: In the fourth quarter of 2022 full year 2023, non-GAAP operating income was 4.37 billion compared to 4.79 billion in 2022 fourth quarter 2023 effective tax rate of 16.3% reflects an increase in our 2023 U S. R&D tax credits this bench.

Charlie Wagner: If it lowered the Q4 rate and brought the full year 2023 effective tax rate to 19.4% slightly below our guidance range of 20% to 21%.

Charlie Wagner: Fourth quarter, 2023, and non-GAAP earnings per share were $4.20, representing 12% growth compared to $3.76 in the fourth quarter of 2022.

4th quarter 2023 in non-GAAP earnings per share were $4.20, representing 12% growth compared to $3.76 in the 4th quarter of 2022. Full year 2023 non-GAAP earnings per share were $15.23, compared to $14.88 in 2022. We ended the quarter with $13.7 billion in cash and investments. Our priorities for cash deployment remain unchanged, as we continue to prioritize investment in innovation including external innovation via business development. During 2023, we completed 10 transactions and recognized over $500 million of AIP R&D. We also deployed over $400 million to repurchase $1.3 million shares over the course of 2023.

Charlie Wagner: Full year 2023, non-GAAP earnings per share were $15.23 compared to $14.88 in 2022.

Charlie Wagner: We ended the quarter with $13 7 billion in cash and investments our priorities for cash deployment remain unchanged as we continue to prioritize investment in innovation, including external innovation via business development. During 2023 we completed 10 transactions and recognized over $500 million of AIP R&D.

Charlie Wagner: We also deployed over $400 million to repurchase one 3 million shares over the course of 2023.

Charlie Wagner: Now, switching to guidance. For 2024, we expect total product revenue in a range of $10.55 to $10.75 billion, representing revenue growth of 8% at the midpoint at current exchange rates. Included in this outlook is our expectation for continued growth in CF as we continue to reach more patients, including younger ones, in core markets and select other countries. Guidance also includes contribution from the commercial launch of CASGEVY in approved indications and geographies. We continue to expect a foundational year for CASGEVY in 2024 as we ramp up patient initiations and build toward a multi-billion dollar market opportunity overtime. We're providing total product revenue guidance rather than specifics by disease area or product, given the inherent uncertainty of new launches as well as the significant disparity in size of our established CF business relative to other revenues.

Now, switching to guidance. For 2024, we expect total product revenue in a range of $10.55 to $10.75 billion, representing revenue growth of 8% at the midpoint at current exchange rates. Included in this outlook is our expectation for continued growth in CF as we continue to reach more patients, including younger ones, in core markets and select other countries. Guidance also includes contribution from the commercial launch of CASGEVY in approved indications and geographies. We continue to expect a foundational year for CASGEVY in 2024 as we ramp up patient initiations and build toward a multi-billion dollar market opportunity overtime.

Charlie Wagner: One's in core markets and select other countries.

Charlie Wagner: Guidance also includes contribution from the commercial launch of course, Chevy and approved indications and geographies. We continue to expect a foundational year for cast JV in 'twenty 'twenty four as we ramp up patient initiations and build toward a multibillion dollar market opportunity overtime, we're providing total product revenue guidance.

We continue to expect a foundational year for CASGEVY in 2024 as we ramp up patient initiations and build toward a multi-billion dollar market opportunity overtime. We're providing total product revenue guidance rather than specifics by disease area or product, given the inherent uncertainty of new launches as well as the significant disparity in size of our established CF business relative to other revenues.

We continue to expect a foundational year for CASGEVY in 2024 as we ramp up patient initiations and build toward a multi-billion dollar market opportunity overtime.

We're providing total product revenue guidance rather than specifics by disease area or product, given the inherent uncertainty of new launches as well as the significant disparity in size of our established CF business relative to other revenues. As a reminder, on the accounting for CASGEVY and the CRISPR profit share arrangement, Vertex will book 100% of revenues for CASGEVY. The profit share with CRISPR, calculated after product and commercial costs, will be recorded in cost of goods sold. Any ongoing research and development costs will be recorded in operating expenses net of CRISPR's share. For total Vertex operating expenses, we project $4.3 to $4.4 billion in full year 2024, combined non-GAAP SG&A, R&D and acquired IP R&D. This operating expense range includes approximately $125 million in currently anticipated IP R&D charges. We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. Note that the costs for multiple Phase III studies have been a significant driver of our growth in our total operating expenses in recent years. Given that a number of Phase III studies were completed as entered 2024, we were able to fund new additional Phase III studies without the same rate of growth in operating expenses.

Other than specifics by disease area or product given the inherent uncertainty of new launches as well as the significant disparity in size of our established CF business relative to other revenues as.

Charlie Wagner: As a reminder, on the accounting for cast JV and the CRISPR profit share arrangement vertex will book, 100% of revenues for cast gebbie, the profit share with CRISPR calculated after product and commercial costs will be recorded in cost of goods sold.

Charlie Wagner: Any ongoing research and development costs will be recorded in operating expenses net of CRISPR share for total vertex operating expenses. We project 4.3 to 4.4 billion in full year 'twenty 'twenty four combined non-GAAP SG&A R&D and acquired IP R&D. This operating expense range includes approximately.

share. For total Vertex operating expenses, we project $4.3 to $4.4 billion in full year 2024, combined non-GAAP SG&A, R&D and acquired IP R&D. This operating expense range includes approximately $125 million in currently anticipated IP R&D charges. We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. Note that the costs for multiple Phase III studies have been a significant driver of our growth in our total operating expenses in recent years. Given that a number of Phase III studies were completed as entered 2024, we were able to fund new additional Phase III studies without the same rate of growth in operating expenses.

share.

For total Vertex operating expenses, we project $4.3 to $4.4 billion in full year 2024, combined non-GAAP SG&A, R&D and acquired IP R&D. This operating expense range includes approximately $125 million in currently anticipated IP R&D charges. We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. Note that the costs for multiple Phase III studies have been a significant driver of our growth in our total operating expenses in recent years. Given that a number of Phase III studies were completed as entered 2024, we were able to fund new additional Phase III studies without the same rate of growth in operating expenses.

Charlie Wagner: $125 million in currently anticipated IP R&D charges.

Charlie Wagner: We continue to invest a majority of our operating expenses into R&D given the momentum in our multiple mid and late stage clinical development programs note that the costs for multiple phase III studies have been a significant driver of our growth in our total operating expenses in recent years given that a number of phase III studies were completed as of.

Given that a number of Phase III studies were completed as entered 2024, we were able to fund new additional Phase III studies without the same rate of growth in operating expenses. While we have substantially completed our commercial investments for CASGEVY, we're also funding the expansion of our commercial capabilities in anticipation of other multi-billion dollar opportunities, represented by our programs with near-term launch potential, while continuing to leverage an attractive business model afforded by our focus in specialty markets. With a more normalized impact from US R&D tax credits in 2024, our full year 2024 non-GAAP effective tax rate is expected to be in the range of 20% to 21%.

Charlie Wagner: We entered 2024, we were able to fund new additional phase III studies without the same rate of growth in operating expenses.

Charlie Wagner: While we have substantially completed our commercial investments for cast Gebbie. We're also funding the expansion of our commercial capabilities in anticipation of other multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by our focus in specialty markets with a more normalized.

Charlie Wagner: <unk> from U S. R&D tax credits in 2024, our full year 2024, non-GAAP effective tax rate is expected to be in the range of 20% to 21%.

Charlie Wagner: In closing, Vertex delivered excellent results yet again in 2023, achieving strong revenue growth, important regulatory approvals and commercial launches and positive pivotal trial results that will enable additional near-term launches. We also made progress in our earlier stage pipeline, with proof of concept for VX-548 in neuropathic pain and anticipated advancement of two additional disease areas into the clinic. We also made substantial investments behind our programs and commercial capabilities for near-term launches. As we head into 2024, we anticipate further important milestones -- as highlighted on slide 20 -- to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls and I'll ask Susie to begin the Q&A period.

In closing, Vertex delivered excellent results yet again in 2023, achieving strong revenue growth, important regulatory approvals and commercial launches and positive pivotal trial results that will enable additional near-term launches. We also made progress in our earlier stage pipeline, with proof of concept for VX-548 in neuropathic pain and anticipated advancement of two additional disease areas into the clinic. We also made substantial investments behind our programs and commercial capabilities for near-term launches. As we head into 2024, we anticipate further important milestones -- as highlighted on slide 20 -- to mark our continued progress in multiple disease areas.

Charlie Wagner: Pathic pain and anticipated advancement of two additional disease areas into the clinic. We also made substantial investments behind our programs and commercial capabilities for near term launches.

Charlie Wagner: As we head into 'twenty 'twenty four we anticipate further important milestones as highlighted on slide 20 to Mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls and I'll ask Susie to begin the Q&A period.

We look forward to updating you on our progress on future calls and I'll ask Susie to begin the Q&A period.

Susie Lisa: Thanks, Charlie. Just to note, given the multiple positive updates this quarter and that's the longer duration of our prepared remarks, we plan to go to about 5:40 this evening. So, it's allowed 30 minutes for your questions. Chuck, please go ahead and assemble the queue.

Operator: Thank you. We will begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at anytime your question has been addressed and you would like to withdraw your question, please press star then 2. And at this time, we'll pause momentarily to assemble our roster.

Susie Lisa: And the first question will come from Ms. Salveen Richter with Goldman Sachs. Please go ahead.

Salveen Richter: Good morning, Thanks for taking my question congratulations on the data and two questions for me one is with regard to. The initial patient you'll be targeting with the next generation CF program could you just elaborate whether its switch patients or patients have discontinued naive patients here and where you anticipate the most demand. Then secondly on the cats Jaffe launch in late.

Salveen Richter: Good morning, thanks for taking my question. Congratulations on the data. Two questions for me, one is with regard to the initial patient you'll be targeting with the next generation CF program, could you just elaborate whether its switched patients or patients who've discontinued, naive patients here and where you anticipate the most demand.

Salveen Richter: The initial patient you'll be targeting with the next generation CF program could you just elaborate whether its switch patients or patients have discontinued naive patients here and where you anticipate the most demand.

Salveen Richter: Then secondly on the cats Jaffe launch in late.

And then secondly, on the CASGEVY launch -- in light of the innovation Cell and Gene Therapy Access Demonstration Model, how do you work that into the launch at this point and is there an overhang as you have to determine how these outcome-based agreements may play out? Thank you.

Salveen Richter: <unk>.

Salveen Richter: Innovation cell and gene therapy access demonstration model and how do you work that into the launch at this point and is there an overhang as you have to determine and how these outcome based agreements may play out. Thank you.

Reshma Kewalramani: Sure thing, Salveen. Let me turn it over to Stuart for both the question on VANZA commercialization and on the CASGEVY launch, with a focus on the CMMI question.

Let me turn it over to Stuart for both the question on vans, the commercialization and on the cash Chevy launched with a focus on the CMI question.

Stuart A. Arbuckle: Yeah, Salveen. So, in answer to your first question on VANZACAFTOR, the answer is both. I think VANZACAFTOR is going to be an attractive treatment option, both for patients who are currently being treated, who might want superior control of their CFTR function -- because both patients and physicians know that CFTR function and dysfunction is the underlying cause of CF and so, if you can further improve CFTR function, you're going to get better clinical outcomes down the line. I think we're going to see interest from those who are currently being treated but I also think we're going to see a lot of interest from patients who've previously discontinued one of our CFTR modulators, given the profile that we've demonstrated today. And then on CASGEVY, a couple of comments, really. The first one is I would make is, we're very excited about the demo and the opportunity to work with CMS, for those states who are interested in working with CMS and our institute-outcomes based agreements. I don't particularly see that being a delay, for a couple of reasons. One, we're already working with many state Medicaid agencies, we're not waiting for the demo before we secure access for patients who are covered by Medicaid. And then secondly, in terms of do I think it's going to be complex

Yeah, Salveen. So, in answer to your first question on VANZACAFTOR, the answer is both. I think VANZACAFTOR is going to be an attractive treatment option, both for patients who are currently being treated, who might want superior control of their CFTR function -- because both patients and physicians know that CFTR function and dysfunction is the underlying cause of CF. And so, if you can further improve CFTR function, you're going to get better clinical outcomes down the line. I think we're going to see interest from those who are currently being treated but I also think we're going to see a lot of interest from patients who've previously discontinued one of our CFTR modulators, given the profile that we've demonstrated today.

Stuart Arbuckle: Yeah, Salveen. So, in answer to your first question on VANZACAFTOR, the answer is both. I think VANZACAFTOR is going to be an attractive treatment option, both for patients who are currently being treated, who might want superior control of their CFTR function -- because both patients and physicians know that CFTR function and dysfunction is the underlying cause of CF.

Stuart A. Arbuckle: The answer is both I think vans a cap there is going to be an attractive treatment option. Both for patients who are currently being treated who might want.

Stuart A. Arbuckle: Superior control of the CFT, our function because both patients and physicians know that CFT, our function and dysfunction as the underlying cause of CF and so if you can further improve see FTR function youre going to get better.

And so, if you can further improve CFTR function, you're going to get better clinical outcomes down the line. I think we're going to see interest from those who are currently being treated but I also think we're going to see a lot of interest from patients who've previously discontinued one of our CFTR modulators, given the profile that we've demonstrated today.

Stuart A. Arbuckle: Better clinical outcomes down the line. So I think we're going to see interest from those who are currently being treated but I also think we're going to see a lot of interest from patients who've previously discontinued one of Aussie FTR modulators, given the profile that we've demonstrated today and then on cash Jimmy a couple of comments really the first one I would make is we're very excited.

And then on CASGEVY, a couple of comments, really. The first one is I would make is, we're very excited about the demo and the opportunity to work with CMS, for those states who are interested in working with CMS and our institute-outcomes based agreements. I don't particularly see that being a delay, for a couple of reasons. One, we're already working with many state Medicaid agencies, we're not waiting for the demo before we secure access for patients who are covered by Medicaid. And then secondly, in terms of do I think it's going to be complex and be a delay to negotiate outcomes-based agreements -- I don't really. If you look at the profile of CASGEVY, it is so incredibly strong that, really, we're talking about an outcomes-based agreement which is looking at whether a very, very small number of patients may not respond. And so, I don't think it's an outcomes-based agreement where there's lots of uncertainty and difficulty with the outcomes and metrics and endpoint. I don't expect that to be particularly challenging.

Speaker Change: I could about the demo and the opportunity to work with CMS for those states who are interested.

Speaker Change: In working with CMS and Orange student outcomes based agreements I don't particularly see that being a delay for a couple of reasons. One we're already working with many state Medicaid agencies were not waiting for the demo before we secure access for patients who are covered by Medicaid and then secondly in terms of do I think it's going to be.

And then secondly, in terms of do I think it's going to be complex and be a delay to negotiate outcomes-based agreements -- I don't really. If you look at the profile of CASGEVY, it is so incredibly strong that, really, we're talking about an outcomes-based agreement which is looking at whether a very, very small number of patients may not respond. And so, I don't think it's an outcomes-based agreement where there's lots of uncertainty and difficulty with the outcomes and metrics and endpoint. I don't expect that to be particularly challenging.

Speaker Change: Next would be a delay to negotiate outcomes based agreements I don't really if you look at the profile.

Speaker Change: All cash JV. It is so incredibly strong that really we're talking about an outcomes based agreement, which is looking at whether a very very small number of patients may not respond and so I don't think it's an outcomes based agreement, where there's lots of uncertainty and difficulty with the outcomes and metrics and endpoint. So I don't expect that.

Speaker Change: To be particularly challenging.

Salveen Richter: Thank you.

Operator: The next question will come from Geoff Meacham with Bank of America. Please go ahead.

Geoff Meacham: Hey, guys. Thanks so much for the question and congrats on the data. On VANZA, I just have a couple of questions. Can you follow SKYLINE or RIDGEINE in an extension? I'm just trying to think if you can pick up more differentiation versus TRIKAFTA, just in terms of maybe exacerbations or for measuring pancreatic sufficiency over a longer period. I guess, ultimately, where I'm going is that sweat chloride isn't widely used in the clinic for treatment decisions so, I'm trying to see rationale for maybe switching a patient away from TRIKAFTA if they're stable. Thank you.

And then I just have a couple of questions can you follow skyline or ridge line and an extension I'm just trying to think if we can pick up more differentiation versus strike catheter just informed in terms of maybe exacerbations or for measuring pancreatic sufficiency over a longer period, I guess, ultimately where I'm going is that sweat chloride isn't right.

Geoff Meacham: Used in the clinic for treatment decisions. So I'm trying to see rationale for maybe switching a patient away from Tricast.

Speaker Change: If they're stable thank you.

Reshma Kewalramani: Yeah. Hey thanks, Geoff. This is Reshma, let me take that one.

Ian F. Smith: When we think about the patients who were enrolled in both the SKYLINE trials, so the 12-year olds and above and the RIDGELINE patients, 6 to 11 -- there are already extension studies so, those patients have the opportunity to roll over into open label extension studies, just like we did with TRIKAFTA. And I do suspect you're right about the ability to evaluate and document the overall improvements in patients with CF lives over time. And just to give you a sense for what I'm looking at and why I say that, if you look in the safety tables that were one of the slides-- unsurprisingly, the most common, or one of the most common, AEs in this patient population is pulmonary exacerbation. And if you look, there are less pulmonary exacerbations numerically, in those safety table, in the patients on VANZA than on the patients who are on TRIKAFTA. And TRIKAFTA is an amazing drug that is already documented improvements in pulmonary exacerbation and other longer term outcomes. So, I do think you're very correct that we will be able to pick up these long-term outcomes as these patients are followed in the open label extension studies and then, as they are followed in registries. And we are very fortunate in CF that the registries already exist and the vast majority of patients with cystic fibrosis are followed in registries.

When we think about the patients who were enrolled in both the SKYLINE trials, so the 12-year olds and above and the RIDGELINE patients, 6 to 11 -- there are already extension studies so, those patients have the opportunity to roll over into open label extension studies, just like we did with TRIKAFTA. And I do suspect you're right about the ability to evaluate and document the overall improvements in patients with CF lives over time.

Ian F. Smith: Suspect you're right about the ability to evaluate and document the overall improvements in patients with CF lives over time.

And just to give you a sense for what I'm looking at and why I say that, if you look in the safety tables that were one of the slides-- unsurprisingly, the most common, or one of the most common, AEs in this patient population is pulmonary exacerbation. And if you look, there are less pulmonary exacerbations numerically, in those safety table, in the patients on VANZA than on the patients who are on TRIKAFTA. And TRIKAFTA is an amazing drug that is already documented improvements in pulmonary exacerbation and other longer term outcomes. So, I do think you're very correct that we will be able to pick up these long-term outcomes as these patients are followed in the open label extension studies and then, as they are followed in registries. And we are very fortunate in CF that the registries already exist and the vast majority of patients with cystic fibrosis are followed in registries.

Ian F. Smith: And just to add to. To give you a sense for what I'm looking at and why I say that if you look at the safety tables that were one of the slides. Unsurprisingly, the most common or one of the most common aes in this patient population is pulmonary exacerbation and if you look there are less pulmonary exacerbations numerically and those safety table in the patients on vans that then and the patients who are on track CAFTA and try CAFTA is an. <unk> drug that is already documented improvements in pulmonary exacerbation and other longer term outcomes. So I do think you're very correct that we will be able to pick up. These long term outcomes. As these patients are followed in the open label extension studies and then as they are followed in registries and we are very fortunate in CF. The registry is already exist and the vast majority of patients with cystic fibrosis are followed in registries.

To give you a sense for what I'm looking at and why I say that if you look at the safety tables that were one of the slides.

Ian F. Smith: Unsurprisingly, the most common or one of the most common aes in this patient population is pulmonary exacerbation and if you look there are less pulmonary exacerbations numerically and those safety table in the patients on vans that then and the patients who are on track CAFTA and try CAFTA is an.

<unk> drug that is already documented improvements in pulmonary exacerbation and other longer term outcomes. So I do think you're very correct that we will be able to pick up. These long term outcomes. As these patients are followed in the open label extension studies and then as they are followed in registries and we are very fortunate in CF.

So, I do think you're very correct that we will be able to pick up these long-term outcomes as these patients are followed in the open label extension studies and then, as they are followed in registries. And we are very fortunate in CF that the registries already exist and the vast majority of patients with cystic fibrosis are followed in registries.

Ian F. Smith: The registry is already exist and the vast majority of patients with cystic fibrosis are followed in registries.

Geoff Meacham: Thank you.

Operator: The next question will come from Mohit Bansal with Wells Fargo. Please go ahead.

Mohit Bansal: Great. Thank you very much for taking my question. Just following up on Geoff's question, how commonly doctors check sweat chloride levels as part of -- I know it is for diagnostic purposes but do they retest it for prescribing as well or it is something that you will have to educate these doctors on that? And then my follow up is actually on the COGS for Charlie, cost of goods store. As you think about 2024 or what happened in 4th quarter -- was it one-time movement from R&D to COGS which drove it or is it something that we need to continue modeling going forward? Thank you.

Mohit Bansal: Following up on.

Mohit Bansal: Jeffs question.

Mohit Bansal: Commonly doctor checks sweat chloride levels as part of I know it is for diagnostic purposes, but due detected for retested for prescribing Enzo or something that you will have to educate these doctors on that and then my follow up is actually on the call for Charlie.

Mohit Bansal: Cost of goods store as you think about 2024 or what happened in 'twenty 'twenty fourth quarter was a one time a woman from R&D to Cogs.

Mohit Bansal: Which drove it.

Mohit Bansal: It's something that we need to continue modeling going forward. Thank you.

Reshma Kewalramani: Hey. Hi, Mohit, let me ask Charlie to tackle the COGS question first and I'll come back and tell you about sweat chloride in clinical practice.

Charles Wagner: Yeah, Mohit. In the 4th quarter, because CASGEVY was approved in the US, we started treating it as a commercial product. And therefore, we took some of the manufacturing costs that previously had been recorded in R&D and moved them up to cost of goods sold. Those manufacturing costs will remain in cost of goods sold, going forward.

Charlie Wagner: <unk> was approved in the U S. We started treating it as a commercial product and therefore, we took some of the manufacturing costs that previously had been recorded in R&D and move them up to cost of goods sold those manufacturing costs will remain in cost of goods sold going forward.

Reshma Kewalramani: Well, with regard to sweat chloride measurement in clinical practice, you're very correct. In terms of diagnosis, patients in the western world are diagnosed by a gene test -- a genetic test, oftentimes when patients are born -- or when people are born -- and then, that's confirmed with a sweat chloride test. If the number's above 60, that's a diagnosis of CF; if it's between 30 and 60 millimole for sweat chloride, that's indeterminate and if it's less than 30, that is not diagnosed as CF.

Charlie Wagner: 60 that the diagnosis of CF, if it's between 30 and 60 million MAU for sweat chloride, that's indeterminate and.

Charlie Wagner: If it's less than 30 that is not.

Charlie Wagner: Diagnosed as CEA.

Charlie Wagner: This is not a metric, sweat chloride is not a measure that's followed routinely in clinical practice but what physicians understand very well, especially pulmonologists who are CF experts, is that the underlying cause of disease in CF is dysfunction of the CFTR protein. That's very well understood. And further, that a direct readout of that CFTR protein function, is sweat chloride. So, I think the concepts are very well understood but sweat chloride, other than the diagnosis, is not a commonly used test in the clinic.

Charlie Wagner: This is not a metric sweat chloride is not a measure that's followed routinely in clinical practice, but what physicians understand very well, especially pulmonologists, who are CF experts is that the underlying cause of disease. In CF is this function of this the FTR protein.

Charlie Wagner: That's very well understood.

Charlie Wagner: And further that a direct readout of that see FTR protein function is sweat chloride. So I think the concepts are very well understood, but sweat chloride other than the diagnosis is not a commonly used test.

Charlie Wagner: In the clinic.

Mohit Bansal: Got it.

Operator: The next question will come from Phil Nadeau with TD Cowen. Please go ahead.

TD Cowen: Good afternoon. Let us add our congratulations on another positive pivotal program. One on sweat chloride and then one actually on the pain data that you released last week. First, on the sweat chloride. It does look like TRIKAFTA gets a decent proportion of patients to below 60 millimole per liter and below 30 Millimole per liter, do you have data following patients who've been on TRIKAFTA for a long time to show better outcomes for those TRIKAFTA patients who got to low levels of sweat chloride, which then, presumably, you could extrapolate to the VANZA Triple and show a higher proportion of patients would have good outcomes.

Phil Nadeau: Good afternoon. Let us add our congratulations on another positive pivotal program. One on sweat chloride and then one actually on the pain data that you released last week.

TD Cowen: One on <unk>.

Alrighty, then one actually on the pain data that you released last week firsthand the sweat chloride.

First, on the sweat chloride. It does look like TRIKAFTA gets a decent proportion of patients to below 60 millimole per liter and below 30 millimole per liter -- do you have data following patients who've been on TRIKAFTA for a long time, to show better outcomes for those TRIKAFTA patients who got to low levels of sweat chloride? Which then, presumably, you could extrapolate to the VANZA Triple and show a higher proportion of patients would have good outcomes.

TD Cowen: Does look like truck after gets a decent proportion of patients to below 60, millimole per liter and below 30 Millimole per liter do you have data following patients who've been on track after for a long time to show better outcomes for the strike half the patients who got to low levels of sweat chloride, which then presumably you could extrapolate to the fans of tripling.

TD Cowen: So a higher proportion of patients would have good outcomes.

TD Cowen: That's first question and then, the second question on the pain data released last week. It does seem like the bunionectomy Phase II trial underperformed the Phase IIs previously released as well as the abdominoplasty Phase III released last week. Was there anything different about the trial which would have caused 548 to act less potently there than it had in the prior studies? Thanks.

TD Cowen: <unk> performed the phase twos previously released as well as the Abdominoplasty Phase three released last week was there anything different about the trial, which would have caused five for it to act.

TD Cowen: Less potently there than it had in the prior studies. Thanks.

Reshma Kewalramani: Yup. Phil, let me take bunionectomy, abdominoplasty, VX-548 first and then, we'll come back to sweat chloride.

TD Cowen: Phil I'll, let me take bank enacted me Abdominoplasty VX five for a first and then we'll come back to sweat chloride.

Speaker Change: You know what I actually find remarkable, Phil, is how consistently 548 has performed. That, to me, is more striking than the smaller differences in bunionectomy read out Phase II to Phase III or across from bunionectomy to abdominoplasty. So, if I look at the totality of the VX-548 evidence -- and it's easy enough to do because the structure of the study design was very similar in Phase II as Phase III and we have the same dose to high dose in Phase II -- you'll see that bunionectomy and abdominoplasty performed virtually identically. Like the SPID48 was something like 40 points or something like that, I think that was the actual number. And then when you move to Phase III, again, positive studies against placebo. In the grand scheme of things, this is remarkable because as you know, the conduct of clinical trials in the pain field is notoriously difficult. Placebo effects move around significantly, the effect of any comparator group moves around significantly. So, when I look at the totality of the data -- and for me, that means looking at the data from Phase II to Phase III and it also means looking at the SPID48, let's focus in bunionectomy -- and connecting that with the NPRS. Remember the NPRS is the actual score that feeds the SPID48, which is an integration of NPRS overtime. If you look at the NPRS data, the decrease in the NPRS is three points, four points in bunionectomy; it's three points, four points in abdominoplasty, start to hour 48.

You know what I actually find remarkable, Phil, is how consistently 548 has performed. That, to me, is more striking than the smaller differences in bunionectomy read out Phase II to Phase III or across from bunionectomy to abdominoplasty. So, if I look at the totality of the VX-548 evidence -- and it's easy enough to do because the structure of the study design was very similar in Phase II as Phase III and we have the same dose to high dose in Phase II -- you'll see that bunionectomy and abdominoplasty performed virtually identically. Like the SPID48 was something like 40 points or something like that, I think that was the actual number.

Speaker Change: That to me is more striking than the smaller differences in bunionectomy read out phase II to phase III or across from Bunionectomy. Two abdominoplasty. So if I look at the totality of the VX 548 evidence and it's easy enough to do.

Speaker Change: Cause the structure of the study design was very similar in phase two as phase III and we have the same dose to high dose in phase two you'll see that bunion ectomere, an abdominoplasty performed virtually identically like the.

Speaker Change: The the split 48 was something like 40 points or something like that I think that was the actual number and then when you move to phase three again positive studies against placebo in the Grand scheme of things. This is remarkable because as you know.

And then when you move to Phase III, again, positive studies against placebo. In the grand scheme of things, this is remarkable because as you know, the conduct of clinical trials in the pain field is notoriously difficult. Placebo effects move around significantly, the effect of any comparator group moves around significantly. So, when I look at the totality of the data -- and for me, that means looking at the data from Phase II to Phase III and it also means looking at the SPID48, let's focus in bunionectomy -- and connecting that with the NPRS. Remember the NPRS is the actual score that feeds the SPID48, which is an integration of NPRS overtime. If you look at the NPRS data, the decrease in the NPRS is three points, four points in bunionectomy; it's three points, four points in abdominoplasty, start to hour 48.

Speaker Change: The conduct of clinical trials in the pain field is notoriously difficult placebo effects move around significantly the effect of any comparator group moves around so significantly so when I look at the totality of the data and for me that means looking at the data from phase II to phase III.

Speaker Change: And it also means looking at the Big 48, let's focus on Bunionectomy inbound inactivate and connecting that with the N. P. R. S. Remember the N. P. Arris is the actual score that feeds the spent 48, which is an integration of N. P. R. S. Overtime. So if you look at the N P. R S data.

If you look at the NPRS data, the decrease in the NPRS is 3.4 points in bunionectomy; it's 3.4 points in abdominoplasty, start to hour 48. And it's about a 50% decrease in terms of the relative decrease. And when you look at that in comparison to NORCO, the opioid we used in the trial, that number 3.2 in abdominoplasty, 3.6 in bunionectomy and it's approximately a 50% reduction in terms of the relative change. So, I put that altogether and I see quite a bit of consistency and very good therapeutic effectiveness and efficacy.

Speaker Change: The decrease in the N. P. R. S is three points four points in Bunionectomy, it's three points four points and Abdominoplasty start to our.

Speaker Change: And it's about a 50% decrease in terms of the relative decrease and when you look at that in comparison to norco. The opioid we used in the trial that number three point to an abdominoplasty three six in Bunionectomy and its approximately a 50% reduction in terms of the realm. Tiv change, so I put that altogether and I see quite a bit of consistency and very good therapeutic effectiveness and advocacy.

Speaker Change: Tiv change, so I put that altogether and I see quite a bit of consistency and very good therapeutic effectiveness and advocacy.

On sweat chloride. So, it's a really, really great question. In order to sort of really understand this, you have to triangulate a couple of different data points. One data point is around just the natural history and the genetics of this disease. Take for example, patients who are FMF versus those who are FRF. FMF patients have very high sweat chloride and have more severe disease. FRF patients, the residual function patients, have relatively better sweat chloride levels and relatively less severe disease. That's one set of data. And then to your point, if you look at intervention data, the data that we have the greatest reduction in ppFEV1, sweat chloride and long-term evidence is TRIKAFTA. And if you compare that to KALYDECO, for example, you can see where TRIKAFTA does even better than KALYDECO. And the best example I can give you is on rate of decline. The TRIKAFTA real world data on rate of decline shows there is no decline. And until we got to TRIKAFTA, what we could show is, we slowed the rate of decline. And so, I have every reason in the world to believe as VANZACAFTOR Triple is used over a longer time point and we get CFTR protein function to higher levels -- and the VANZA Triple has given us the best, highest achieved CFTR protein levels -- I do think we're going to see long-term benefit. And yes, you can do all of that math and triangulation from the available data.

Speaker Change: So it's a really really great question.

Speaker Change: In order to sort of really understand this you have to triangulate a couple of different data points. One data point is around just the natural history and the genetics of this disease. So take for example patients who are F. M F versus those who are F. R. F F MF patients at very high sweat chloride and have more.

Speaker Change: More severe disease at RF patients the residual function patients have EM relative.

Speaker Change: Relatively better sweat chloride levels and relatively less severe disease. That's one set of data and then to your point. If you look at intervention data the data that we have the greatest reduction in P. P. F E V. One.

And then to your point, if you look at intervention data, the data that we have the greatest reduction in ppFEV1, sweat chloride and long-term evidence is TRIKAFTA. And if you compare that to KALYDECO, for example, you can see where TRIKAFTA does even better than KALYDECO. And the best example I can give you is on rate of decline. The TRIKAFTA real world data on rate of decline shows there is no decline. And until we got to TRIKAFTA, what we could show is, we slowed the rate of decline. And so, I have every reason in the world to believe as VANZACAFTOR Triple is used over a longer time point and we get CFTR protein function to higher levels -- and the VANZA Triple has given us the best, highest achieved CFTR protein levels -- I do think we're going to see long-term benefit. And yes, you can do all of that math and triangulation from the available data.

Sweat chloride and long term evidence is strike actor.

Speaker Change: And if you compare that to Kalydeco. For example, you can see we're tried CAFTA does even better than Kalydeco and the Best example, I can give you is our rate of decline.

The TRIKAFTA real world data on rate of decline shows there is no decline. And until we got to TRIKAFTA, what we could show is, we slowed the rate of decline. And so, I have every reason in the world to believe as VANZACAFTOR Triple is used over a longer time point and we get CFTR protein function to higher levels -- and the VANZA Triple has given us the best, highest achieved CFTR protein levels -- I do think we're going to see long-term benefit. And yes, you can do all of that math and triangulation from the available data.

The TRIKAFTA real world data on rate of decline shows there is no decline. And until we got to TRIKAFTA, what we could show is, we slowed the rate of decline.

Speaker Change: The Tri capped our real world data on rate of decline shows there is no decline and until we got to try capture what we could show is we slowed the rate of decline and so I have every reason in the world to believe as the vans. The captor Triple is used over a longer time point and we.

And so, I have every reason in the world to believe as VANZACAFTOR Triple is used over a longer time point and we get CFTR protein function to higher levels -- and the VANZA Triple has given us the best, highest achieved CFTR protein levels -- I do think we're going to see long-term benefit. And yes, you can do all of that math and triangulation from the available data.

Speaker Change: <unk> C F T our protein function to higher levels in the vans, a triple has given us the best.

Speaker Change: Highest achieved CFT our protein.

Speaker Change: Levels I do think we're going to see long term benefit and yes, you can do all of that math and triangulation from the available data.

Phil Nadeau: Perfect. Thank you.

Operator: The next question will come from Robyn Karnauskas with Truist. Please go ahead.

Geoff Meacham: Hi, thank you. So, commercialization -- I know it's really hard switching from one drug to the next, can you walk me through switching from TRIKAFTA to the next drug? Given that people are stable, their lung function are great -- how would you think about what motivates commercial Europe, as well as US, to allow people to stay on drug and move to next generation drugs? And I think I'm coming from the point of like, I remember from a long time ago, that people had a hard time switching from one drug to the other and I want to understand more how you actually help people, help commercial organizations switch from one to the next.

Robyn Karnauskas: Hi, thank you. So, commercialization -- I know it's really hard switching from one drug to the next, can you walk me through switching from TRIKAFTA to the next drug? Given that people are stable, their lung function are great -- how would you think about what motivates commercial Europe, as well as US, to allow people to stay on drug and move to next generation drugs?

Robin Kronos: So.

Geoff Meacham: Commercialization I know, it's really hard switching from one drug to that can you walk me through.

Geoff Meacham: Switching from a cap that you did not next chart. Unlike gives.

Geoff Meacham: Given that people are female their lung function. There are great. How would you think about what motivates.

Geoff Meacham: Commercial.

Geoff Meacham: Europe as well as you are.

Geoff Meacham: Hugh.

Geoff Meacham: <unk> people to stay on drug and like move to next generation drugs.

And I think I'm coming from the point of like, I remember from a long time ago, that people had a hard time switching from one drug to the other and I want to understand more how you actually help people, help commercial organizations switch from one to the next.

And I think I'm coming from the plaintiff like I remember from the lung.

Geoff Meacham: Ago that people at a hard time switching from one drug to the other.

And I Wouldnt.

Geoff Meacham: Understand like more like how you actually have.

Geoff Meacham: People help commercial organization switch from one to the next.

Speaker Change: Stuart? Yeah, Robyn. Thank so I've asked if our experience is a little bit different to that we've seen very rapid.

Reshma Kewalramani: Stuart?

Yeah. Robyn, thanks. So, I must confess, our experience is a little bit different to that. We've seen very rapid transitions from medicines, as we've serially innovated and delivered better and better medicines. And even, for instance, when we introduced TRIKAFTA and patients who had been on KALYDECO, for instance, for a very long time -- and obviously, KALYDECO had set a very, very high bar for efficacy. We did see rapid adoption with TRIKAFTA even in those patients, given that it had a clear benefit-risk profile. So, I think, we've seen relatively rapid transitions for our medicines as we've serially innovated. And interestingly, the design of the study actually gives a proof of the fact that patients can effectively transition from TRIKAFTA to VANZACAFTOR because, as Reshma mentioned in her remarks, the design of the study was to have people stable on four weeks of TRIKAFTA therapy to establish a baseline and they were then randomized to either continue on TRIKAFTA or transition to the VANZACAFTOR. So we have, within the study, real world evidence of people being able to transition. And then you asked me, what do I think is going to motivate people to want to consider the VANZACAFTOR Triple combination? I think it's the benefit-risk profile that we've been able to to demonstrate here, achieving higher levels of sweat chloride reduction than with any of our previous medicines, including now, TRIKAFTA. And the fact that this is a once-a-day therapy. So, as I've said a number of times, I think with this profile, we're going to see a lot of enthusiasm from the CF community.

Stuart Arbuckle: Yeah. Robyn, thanks. So, I must confess, our experience is a little bit different to that. We've seen very rapid transitions from medicines, as we've serially innovated and delivered better and better medicines. And even, for instance, when we introduced TRIKAFTA and patients who had been on KALYDECO, for instance, for a very long time -- and obviously, KALYDECO had set a very, very high bar for efficacy. We did see rapid adoption with TRIKAFTA even in those patients, given that it had a clear benefit-risk profile.

Stewart: Transitions from of medicines, as we see really innovated and delivered better and better medicines and even for instance, when we introduce try CAFTA and patients who had been on Kalydeco for instance for a very long time, and obviously kalydeco had set a very very high bar.

Stewart: For efficacy, we did see rapid adoption with trike after even in those patients given that it had a clear benefit risk profile. So.

So, I think, we've seen relatively rapid transitions for our medicines as we've serially innovated. And interestingly, the design of the study actually gives a proof of the fact that patients can effectively transition from TRIKAFTA to VANZACAFTOR because, as Reshma mentioned in her remarks, the design of the study was to have people stable on four weeks of TRIKAFTA therapy to establish a baseline and they were then randomized to either continue on TRIKAFTA or transition to the VANZACAFTOR. So we have, within the study, real world evidence of people being able to transition. And then you asked me, what do I think is going to motivate people to want to consider the VANZACAFTOR Triple combination? I think it's the benefit-risk profile that we've been able to to demonstrate here, achieving higher levels of sweat chloride reduction than with any of our previous medicines, including now, TRIKAFTA. And the fact that this is a once-a-day therapy. So, as I've said a number of times, I think with this profile, we're going to see a lot of enthusiasm from the CF community.

Stewart: We've seen relatively rapid transitions for our medicines as we've serially innovated and interestingly the design of the study actually gives a proof of the fact that patients can effectively transition from try CAFTA two vans a captive because as rest of the mentioned in her remarks the design.

Stewart: The study was to have people stable on four weeks of Tri CAFTA therapy to establish a baseline and they were then randomized to either continue on tri CAFTA or transition to Davanzo catheter. So we have within the study real world evidence of people being able to transition and then you'll ask me what do I think he's going to motivate people to want to consider.

And then you asked me, what do I think is going to motivate people to want to consider the VANZACAFTOR Triple combination? I think it's the benefit-risk profile that we've been able to to demonstrate here, achieving higher levels of sweat chloride reduction than with any of our previous medicines, including now, TRIKAFTA. And the fact that this is a once-a-day therapy. So, as I've said a number of times, I think with this profile, we're going to see a lot of enthusiasm from the CF community.

Stewart: The vans are capped a triple combination I think it's the benefit risk profile that we've been able to to demonstrate here with achieving higher levels.

Sweat chloride reduction than with any of our previous medicines, including now try CAFTA and the fact that this is a once a day therapy. So as I've said, a number of times I think with this profile, we're going to see a lot of enthusiasm from the CF community.

Robyn Karnauskas: So, follow up question for you is, what about the payers of the governments in Europe? Do they believe in like -- you've had very stable levels of lung function with TRIKAFTA, do you think that people focus on that or do they need more data moving forward?

Speaker Change: Do you think that people focus on like that or do they need more data.

Speaker Change: For it.

Stuart Arbuckle: Well. I mean, I think we've had a long track record of working with payers on cystic fibrosis for, again, of well over a decade now. So, I think there's a significant amount of understanding about the disease. Obviously, we'll be presenting the data to VANZACAFTOR to payers in a compliant manner, at the right time.

Speaker Change: One other thing I would note about the VANZACAFTOR Triple combination, is it's likely to be indicated for a very similar population of patients to TRIKAFTA. Which I do think is going to make this launch from a payer perspective a bit different to previous launches, as you will recall, as you've been on this journey with us for a while. You know, when we launched ORKAMBI, we were moving from kind of single digit numbers of eligible patients to a medicine that could potentially treat up to 50% of CF patients. When we then brought TRIKAFTA forward, we were moving it towards being able to treat 90% of patients. VANZA is going to likely have a very similar label to TRIKAFTA and so, it's not likely to be as scary, I would suggest to payers in terms of the big budget impact here.

One other thing I would note about the VANZACAFTOR Triple combination, is it's likely to be indicated for a very similar population of patients to TRIKAFTA. Which I do think is going to make this launch from a payer perspective a bit different to previous launches, as you will recall, as you've been on this journey with us for a while.

Speaker Change: A note about the the vans the CAFTA Triple combination is it's likely to be indicated for a very similar population of patients to try catheter, which I do think is going to make this launch from a payer perspective, a bit different to previous launches as you will recall.

Speaker Change: As you've been on this journey with us for a while you know when we've launched or can be we were moving from kind of single digit numbers of eligible patients to a medicine that could potentially treat up to 50% of CF patients. When we then brought try caf. The forward, we're moving it towards being able to treat 90% of patients vans or is is going to likely have a very.

You know, when we launched ORKAMBI, we were moving from kind of single digit numbers of eligible patients to a medicine that could potentially treat up to 50% of CF patients. When we then brought TRIKAFTA forward, we were moving it towards being able to treat 90% of patients. VANZA is going to likely have a very similar label to TRIKAFTA and so, it's not likely to be as scary, I would suggest to payers in terms of the big budget impact here.

Speaker Change: Similar label to try catheter and so it's not likely to be as scary I would suggest due to payers in terms of the a big budget impact here.

Robyn Karnauskas: Great. Thank you so much.

Operator: The next question will come from Jessica Fye with JP Morgan. Please go ahead.

Jessica Fye: Great. Good evening, thanks for taking my question. Can you set expectations around how you see the cadence of patients initiating the CASGEVY journey, for us? Thank you.

Jessica Fye: Thanks for taking my question.

Jessica Fye:

Jessica Fye: Can you set expectations around how you see the cadence of patients initiating the.

Jessica Fye: Thank you.

Reshma Kewalramani: Sure thing. Stuart?

Yeah, Jess. I think, you know, we've described the patient journey for CASGEVY. It has kind of these multiple phases, from patients being evaluated by their physician and deciding with their physician that this is a journey that they want to go on. You then have to go through the cell culture [inaudible] like manufacturing process and then the cells are infused. Each of those steps can take a number of months and, as you know, we've said that we'll be recognizing revenue at the point of infusion. So, in contrast to our cystic fibrosis launches, which have really seen incredibly rapid uptake, we have said that we are expecting this launch to be more like a traditional biopharma launch. But we are expecting this and we have said we are expecting this to be a foundational year for us as we build momentum around CASGEVY. Having said that, in terms of the destination, we continue to believe that the destination for CASGEVY is it's going to be used in thousands of patients and represents a multi-billion dollar opportunity.

Stuart Arbuckle: Yeah, Jess. I think, you know, we've described the patient journey for CASGEVY. It has kind of these multiple phases, from patients being evaluated by their physician and deciding with their physician that this is a journey that they want to go on. You then have to go through the cell culture [inaudible] like manufacturing process and then the cells are infused. Each of those steps can take a number of months and, as you know, we've said that we'll be recognizing revenue at the point of infusion.

Jeff: You know we've described the patient journey forecast JV. It has kind of these multiple.

Jeff: <unk> from patients being evaluated by their physician and deciding with their physician that this is a journey that they want to go on.

You then have to go through the cell culture.

Jeff: Like in your factory in protest and then are.

Jeff: The cells are infused each of those steps can take a number of months and as you know we've said that we'll be recognizing revenue at the point of infusion. So in contrast to our cystic fibrosis launches, which have really seen incredibly rapid.

So, in contrast to our cystic fibrosis launches, which have really seen incredibly rapid uptake, we have said that we are expecting this launch to be more like a traditional biopharma launch. But we are expecting this and we have said we are expecting this to be a foundational year for us as we build momentum around CASGEVY. Having said that, in terms of the destination, we continue to believe that the destination for CASGEVY is it's going to be used in thousands of patients and represents a multi-billion dollar opportunity.

Jeff: The uptake we have said that we are expecting this launch to be more like a traditional.

Jeff: Bio pharma launch, but we are expecting this and we have said we are expecting this to be a foundational year for us as we build momentum around cash JV.

Jeff: Having said that in terms of the destination. We continue to believe that the destination for cash do you have easy it's going to be used in thousands of patients and represents a multibillion dollar opportunity.

Jessica Fye: Thank you.

Speaker Change: Okay.

Operator: The next question will come from Evan Seigerman with BMO Capital. Please go ahead.

Evan Seigerman: Hi, guys. Thank you so much for taking my question. I know there's a lot on the VANZA Triple but kind of the -- can you maybe walk us through some of the clinical considerations as you would get to, maybe have a physician switch a patient? And then, thinking about potential TRIKAFTA quitters returning on drug, what does that conversation look like and I guess, maybe more specifically, why would a patient discontinue TRIKAFTA and why would they want to re-initiate with the VANZA Triple? Thank you.

Evan Seigerman: Can you maybe walk us through.

Evan Seigerman: Some of the clinical considerations as you would get to maybe have a physician switch a patient and then thinking about kind of potential.

Evan Seigerman: Potential bycatch quitters, returning on drug what does that conversation looked like and I guess, maybe more specifically why would a patient discontinued tricast and why would they want to re initiate with the vantage triple. Thank you.

Reshma Kewalramani: Sure thing, Evan. I think Stuart has talked about this. And maybe I'll shorthand it by saying, we have the approximately 6,000 patients who are in the system, they are known to have CF, they're seen by a CF provider, they used to be on TRIKAFTA -- so, they're not lost. They simply have discontinued it either because of an adverse event or perhaps because of compliance. TRIKAFTA [inaudible], VANZA is, of course, once a day.

Speaker Change: And maybe I'll shorthand it by saying.

Speaker Change: We have the approximately 6000 patients who are in the system. They are known to have C. F. They are seen by a CF provider they used to be on track. After so they're not lost they simply have discontinued it either because of an adverse event.

Speaker Change: <unk> or perhaps because of compliance track.

Speaker Change: Vans is a force once a day so we see those 6000 patients potentially coming back and. The short version of the conversation would be they're coming to see their doctor usually CF patients are seen by their doctor once a quarter. So when they return the conversation might be something like if and when vans is approved there is a new drug.

Vans is a force once a day

So, we see those 6,000 patients potentially coming back and the short version of the conversation would be, they're coming to see their doctor -- usually CF patients are seen by their doctor once a quarter. So, when they return, the conversation might be something like -- if and when VANZA is approved -- there is a new drug, it has this safety, it has this efficacy, do you want to try it? You had tried a medicine before, this is a new one -- and the doctor and patient would have a communication about that. The patients who are already on TRIKAFTA and are doing well, I suspect it's going to be just like it was

Speaker Change: The short version of the conversation would be they're coming to see their doctor usually CF patients are seen by their doctor once a quarter. So when they return the conversation might be something like if and when vans is approved there is a new drug.

Speaker Change: It has this safety. It has this efficacy do you want to try it you had tried a medicine before this is a new one and the doctor and patient would have a communication about that so the patients who are already on untried CAFTA and are doing well I suspect it's going to be just like it.

The patients who are already on TRIKAFTA and are doing well, I suspect it's going to be just like it was from SYMDEKO and ORKAMBI to TRIKAFTA or from KALYDECO to TRIKAFTA. Our CF patients are very educated patients. They know what clinical trials are going on, they know what potential medicines might be coming down the pike and they are interested in being treated with the most effective medicine, the medicine with the best benefit risk. And they do this because it is a disease that starts at birth and is with them their entire life. Now, with the life expectancy based on modeled data being in the 80s, I do think the idea that we can get patients to as close to normal as possible, at least we're on that journey with VANZA, is an attractive option for physicians and patients. And I suspect ,that's what that conversation is going to be about.

Speaker Change: Was from <unk> and ORKAMBI to try CAFTA or from Kalydeco to track after our CF patients are very educated patients. They know what clinical trials are going on they know what potential medicines might be coming down the pike and they are interested in being treated.

Speaker Change: The most effective medicine, the medicine with the best benefit risk and they do this because it is a disease that starts at birth and is with them their entire life now with the life expectancy based on modeled data being in the eighties I do think the ideas.

And they do this because it is a disease that starts at birth and is with them their entire life. Now, with the life expectancy based on modeled data being in the 80s, I do think the idea that we can get patients to as close to normal as possible, at least we're on that journey with VANZA, is an attractive option for physicians and patients. And I suspect ,that's what that conversation is going to be about.

Speaker Change: That we can get patients to as close to normal as possible at least we're on that journey with vans is an attractive option for physicians and patients and I suspect that's what that conversation is going to be about.

Operator: The next question will come from Chris Raymond with Piper Sandler. Please go ahead.

Chris Raymond: Great, thanks. And congrats from us as well, on the data. Just two questions if possible. First, maybe on CASGEVY. We've gotten some physician feedback that, of course, access is a barrier to uptake. But maybe a surprise that we got from some of the questions we've asked is the transplant center capacity and prioritization of non-oncology patients is also sort of a consideration. Just curious, as you activate these ATC's, maybe talk about transplant capacity. Does this factor into the discussions as you're activating these sites?

Chris Raymond: From us as well and the data just two questions.

Chris Raymond: Possible first maybe on cash JV.

We've gotten some physician feedback that you know of course.

Chris Raymond: Access is a barrier to uptake.

Chris Raymond: But maybe a surprise that we got from some of the questions. We've asked is the transplant center capacity and prioritization of non oncology patients is also sort of a consideration.

Chris Raymond: Just curious as you activate these atc's maybe talk about transplant capacity.

Chris Raymond: Does this factor into the discussions as you're activating the sites.

And then maybe on VANZACAFTOR. I know you guys have described the royalty differential, I think TRIKAFTA is in the low double digits and you've described VANZACAFTOR as down in the single digits. But are there plans to put some guardrails around this leverage improvement as you get closer to the launch of the VANZA Triple? Thanks.

Chris Raymond: Are there plans to put some guardrails around this leverage improvement as you get closer to the launch of the Denver Triple. Thanks.

Reshma Kewalramani: I'm sorry, Chris. I didn't follow the question on the VANZA Triple, I got you on CASGEVY. Is it about the royalty?

Speaker Change: Is it about right.

Chris Raymond: Yeah, just on the leverage and the royalty differential. I think you guys described the difference but are there plans to put guardrails around that leverages, people model that.

Speaker Change: Difference, but are there plans to put guardrails around them.

Speaker Change: You know around that Leverages people model that Yep Yep sure thing, let me take.

You know around that Leverages people model that

Reshma Kewalramani: Yep, sure thing. Let me take CASGEVY quickly, turn it over to Stuart and then we'll -- just one minute real quick with Charlie and he'll tell you about the royalty structure for VANZA.

Speaker Change: Cast JV quickly turn it over to Stuart and then.

Stuart A. Arbuckle: Well, just one minute real quick with that Charlie and he'll tell you about the royalty structure for vanda.

Stuart A. Arbuckle: A real quickly on cash JV, we have not heard of there being a center capacity issue. And honestly, we have not heard about challenges for reimbursement, we've actually had very positive reception from payers, but I'll turn it over to Stuart to make a quick comment on activation and his perspective, yes, and we're making great. Great progress, Chris I would say activating authorized treatment centers just here in the U S.

Real quickly on CASGEVY, we have not heard of there being a center capacity issue. And honestly, we have not heard about challenges for reimbursement, we've actually had very positive reception from payers. But I'll turn it over to Stuart to make a quick comment on activation and his perspective. Yeah. And we're making great progress, Chris. I would say activating authorized treatment centers just here in the U S. Now up to 12, and I don't think those centers would be going through the the effort of becoming an activated treatment center, if they weren't fully intending to treat patients with cast JV and then as restaurant side.

Stuart A. Arbuckle: And honestly, we have not heard about challenges for reimbursement, we've actually had very positive reception from payers, but I'll turn it over to Stuart to make a quick comment on activation and his perspective, yes, and we're making great.

Stuart Arbuckle: Yeah. And we're making great progress, Chris, I would say, activating authorized treatment centers just here in the US. We're now up to 12 and I don't think those centers would be going through the the effort of becoming an activated treatment center if they weren't fully intending to treat patients with CASGEVY. And then as Reshma said, the reaction we've had from payers has been really positive.

Stuart A. Arbuckle: Great progress, Chris I would say activating authorized treatment centers just here in the U S.

I would say activating authorized treatment centers just here in the U S. Now up to 12, and I don't think those centers would be going through the the effort of becoming an activated treatment center, if they weren't fully intending to treat patients with cast JV and then as restaurant side. The reaction we've had from payers has been really positive.

Stuart A. Arbuckle: Now up to 12, and I don't think those centers would be going through the the effort of becoming an activated treatment center, if they weren't fully intending to treat patients with cast JV and then as restaurant side. The reaction we've had from payers has been really positive.

The reaction we've had from payers has been really positive. I think they are incredibly impressed with the clinical data they are well aware of the unmet need in sickle cell disease, and indeed transfusion dependent thalassemia and the burden that places on on patients and indeed, the health care system. They like the label that we've got and they like our value based pricing. So I've been very encouraged by the conversations we've been having with payers and I'm fully expecting us to be able to secure great access for sickle cell disease and TD T patients.

The reaction we've had from payers has been really positive.

I think they're incredibly impressed with the clinical data, they are well aware of the unmet need in sickle cell disease and indeed, transfusion-dependent thalassemia and the burden that places on patients and indeed, the healthcare system. They like the label that we've got and they like our value-based pricing. So, I've been very encouraged by the conversations we've been having with payers and I'm fully expecting us to be able to secure great access for sickle cell disease and TDT patients.

Stuart A. Arbuckle: I think they are incredibly impressed with the clinical data they are well aware of the unmet need in sickle cell disease, and indeed transfusion dependent thalassemia and the burden that places on on patients and indeed, the health care system.

Stuart A. Arbuckle: They like the label that we've got and they like our value based pricing. So I've been very encouraged by the conversations we've been having with payers and I'm fully expecting us to be able to secure great access for sickle cell disease and TD T patients.

Stuart A. Arbuckle: Charlie a word on royalty that just briefly on the royalties that's christie the blended royalty rate on our current CF portfolio is just under 10%.

Reshma Kewalramani: Charlie, a word on royalties?

Charles Wagner: Just briefly on the royalties. Chris, the blended royalty rate on our current CF portfolio is just under 10%. And so, high single digit, call it. And we expect with the VANZA Triple, that royalty burden will be meaningfully lower in the single digits, no additional color to add today. And then, of course, if you want to model the impact of that, you have to factor in the rate of switching from TRI and other medicines again. So, as we get closer to commercialization, we will have more to say.

Charlie Wagner: And so so high single digit call it and we expect with the vans.

Charlie Wagner: Triple that royalty burden will be meaningfully lower in the single digits no additional color to add today and then of course, if you want to model the impact of that you have to factor in the rate of switching from try and other medicines again, so as we get closer to commercialization, we will have more to say.

Chris Raymond: Thank you.

Operator: The next question will come from Colin Bristow with UBS. Please go ahead.

Colin Bristow: Hey, good evening and congrats on all the data. Maybe first on the VANZA Triple, can you say if there are any cases of AST or ALT elevations greater than three or five times the upper limit of normal? And then just secondly, I see that you've now three follow-on pain assets in the clinic -- 993, 973 and 708. Could you just give us more color on how you expect them to be differentiated and just elaborate a bit more on the strategy from here? Thanks.

Colin Bristow: Maybe first on the vans a triplet can you say if there are any cases of F. L. P elevations greater than three or five times the upper limit of normal and then just secondly, I see that you know three follow on pain assets in the clinic now 93, 973 and 708.

Colin Bristow: Could you just give us more color on how you expect them to be differentiated in and just elaborate a bit more of a strategy from here. Thanks.

Reshma Kewalramani: Yeah. Sure thing, Colin. Quickly on LFT elevations with the VANZACAFTOR Triple. As with all of the CFTR modulators, there are some elevations in LFT's. They're approximately the same with the VANZACAFTOR Triple as with TRIKAFTA.

Speaker Change: On the pain program. Colin, this is exactly what you saw us do in CF. And frankly, what you should expect from us across the portfolio -- and that is to say, a portfolio approach to every disease in our sandbox. If there is any way to improve on our asset, we aim to be the ones who do so. A couple of examples of what we're doing -- with 993, for example. 993 is a medicine that may be able to be dosed both oral and IV and we're pursuing both. We believe that there is a real opportunity here for a patient to come into the hospital and have 993, one of our NaV1.8 inhibitors, be the medicine that they get for pain relief, let's say, intraoperatively. And then when they can take by mouth, then they can switch to 548, 993, as an example. Another example that we're working on -- you know that we also have a pipeline of NaV1.7 inhibitors. Those are still in pre-clinical development but they are making good progress. So, one of the other elements were working on is formulations in terms of drug-drug interactions and the possibility to combine. So, NaV1.7 could be a molecule as a single agent therapy or it could also be a therapy in combination with a NaV1.8. That's kind of a sense for what we're doing with our follow-on approach.

On the pain program. Colin, this is exactly what you saw us do in CF. And frankly, what you should expect from us across the portfolio -- and that is to say, a portfolio approach to every disease in our sandbox. If there is any way to improve on our asset, we aim to be the ones who do so. A couple of examples of what we're doing -- with 993, for example. 993 is a medicine that may be able to be dosed both oral and IV and we're pursuing both. We believe that there is a real opportunity here for a patient to come into the hospital and have 993, one of our NaV1.8 inhibitors, be the medicine that they get for pain relief, let's say, intraoperatively. And then when they can take by mouth, then they can switch to 548, 993, as an example.

If there is any way to improve on our asset we aim to be the ones who do so so a couple of examples of what we're doing with 99 three for example.

Speaker Change: 99, three is a medicine that may be able to be dosed, both oral and IV and were pursuing both we believe that there is a real opportunity here for a patient to come into the hospital and have 90 931 of our NAV one eight inhibitors b the <unk>.

993 is a medicine that may be able to be dosed both oral and IV and we're pursuing both. We believe that there is a real opportunity here for a patient to come into the hospital and have 993, one of our NaV1.8 inhibitors, be the medicine that they get for pain relief, let's say, intraoperatively. And then when they can take by mouth, then they can switch to 548, 993, as an example.

We believe that there is a real opportunity here for a patient to come into the hospital and have 993, one of our NaV1.8 inhibitors, be the medicine that they get for pain relief, let's say, intraoperatively. And then when they can take by mouth, then they can switch to 548, 993, as an example. Another example that we're working on -- you know that we also have a pipeline of NaV1.7 inhibitors. Those are still in pre-clinical development but they are making good progress. So, one of the other elements were working on is formulations in terms of drug-drug interactions and the possibility to combine. So, NaV1.7 could be a molecule as a single agent therapy or it could also be a therapy in combination with a NaV1.8. That's kind of a sense for what we're doing with our follow-on approach.

Speaker Change: Send that they get for pain relief, let's say intra operatively and then when they can take by mouth. Then they can switch to 548993 as an example, another example that we're working on you know that we also have a pipeline of NAV 1.7 inhibitors. Those are still in preclinical developed.

Another example that we're working on -- you know that we also have a pipeline of NaV1.7 inhibitors. Those are still in pre-clinical development but they are making good progress. So, one of the other elements were working on is formulations in terms of drug-drug interactions and the possibility to combine. So, NaV1.7 could be a molecule as a single agent therapy or it could also be a therapy in combination with a NaV1.8. That's kind of a sense for what we're doing with our follow-on approach.

Speaker Change: But they are making good progress so one of the other elements were working on is formulations in terms of drug drug interactions and the possibility to combine so NAV one seven could be a molecule as a single agent therapy or it could also be a therapy in combination.

Speaker Change: <unk> with our NAV one eight that's kind of a sense for what we're doing with our follow on approach.

Speaker Change: Chuck, we'll take one more question, please. Thank you.

Susie Lisa: Chuck, we'll take one more question, please.

Colin Bristow: Thank you.

Operator: Yes, ma'am. Our last question for the evening will come from Myles Minter with William Blair. Please go ahead.

Myles Minter: Hi, thanks for sneaking me in. You just mentioned the first commercial patients on CASGEVY are expected to start the journey in the coming weeks. Can you clarify what geographies they are in and do you have a sense of how many patients you've screened out at those at those ATCs to identify those first patients? Thanks very much.

Reshma Kewalramani: Sure thing. Hey Myles, we're not going to comment in detail on the first patients but as Stuart said in his prepared remarks, we're expecting our first patient shortly.

Myles Minter: Thank you.

Operator: This concludes our question and answer session as well as our conference call for today. I want to thank everyone for attending today's presentation. A replay of today's event will be available shortly after the call concludes by dialing 1-877-344-7529 or 1-412-317-0088, using replay access code 10178829. Thank you and have a great day.

Speaker Change: 170088, using replay access code 101788 to nine thank you and have a great day.

Yes. [music].

Speaker Change: [music].

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