Q3 2023 Vertex Pharmaceuticals Inc Earnings Call

November 6, 2023

Operator: Good day and welcome to the Vertex Pharmaceuticals third quarter 2023 conference call, all participants will be in a listen only mode, should you need assistance please signal a conference specialist by pressing the star key followed by zero, after today's presentation there will be an opportunity to ask questions, please note this event is being recorded, I would now like to turn the conference over to Miss Susie Lisa, please go ahead ma'am.

I would now like to turn the conference over to MS. Susie Lisa. Please go ahead ma'am.

Susie Lisa: Good evening, all my name is Susie Lisa and as the senior Vice President of Investor Relations it is my pleasure to welcome you to our third quarter 2023 financial results conference call, on tonight's call making prepared remarks, we have doctor Reshma Kewalramani Vertex's, CEO and President Stuart Arbuckle, Chief operating Officer, and Charlie Wagner, Chief 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. These statements, including without limitation. Those regarding vertex is marketed cystic fibrosis medicines, our pipeline and vertex is 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'll now turn the call over to Ray Smith.

On tonight's call, making prepared remarks, we have doctor base amount came out of her money for Texas, CEO and President Stuart Arbuckle, Chief operating Officer, and Charlie Wagner, Chief 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.

Susie Lisa: 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. These statements, including without limitation. Those regarding vertex is marketed cystic fibrosis medicines, our pipeline and vertex is 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'll now turn the call over to Ray Smith.

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. These statements, including without limitation. Those regarding vertex is marketed cystic fibrosis medicines, our pipeline and vertex is future financial performance are based on management's current assumptions.

Susie Lisa: These statements, including without limitation those regarding Vertex's marketed cystic fibrosis medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions, cctual 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'll now turn the call over to Ray Smith.

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'll now turn the call over to Ray Smith.

Susie Lisa: 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'll 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've delivered another strong quarter and continue to drive execution across the company, by reaching more CF patients, third quarter global product revenue grew 6% versus the prior year period, and we are raising full year 2023 CF product revenue guidance to approximately $9.85 billion. We are delivering on our marketed medicines and CF, while simultaneously preparing for commercial excellence in multiple areas ahead of a potential near term launches. <unk> extra south in both severe sickle cell disease, and transfusion dependent beta thalassemia VX. VX 548 for acute pain and longer term in peripheral neuropathic pain, and our vans captor triple combination therapy for cystic fibrosis. Most notably we are tracking towards an extra salt producer date for sickle cell disease on December eight of this year and for T. D. T. On March 30th of next year with global regulatory reviews also underway in Europe, and the U K phase III pivotal trial Readouts in early 'twenty 'twenty four from <unk>. Both our vans, a catheter triple in CF and our VX five for a program in acute pain. The phase two trial read out by year end 'twenty 'twenty suite from our VX five for a trial in diabetic peripheral neuropathy and completion of enrollment in the phase two portion of the VX 147 phase two sweet program in a M. Kt later this year with that overview, let me now turn to our pipeline update.

By reaching more CF patients third quarter global product revenue grew 6% versus the prior year period, and we are raising full year 2023 CF product revenue guidance to approximately 9.85 billion.

Reshma Kewalramani: We are delivering on our marketed medicines and CF, while simultaneously preparing for commercial excellence in multiple areas ahead of a potential near term launches including exa-cel in both severe sickle cell disease and transfusion dependent beta thalassemia, VX-548 for acute pain and longer term in peripheral neuropathic pain, and our Vanzacaftor triple combination therapy for cystic fibrosis. Most notably we are tracking towards an extra salt producer date for sickle cell disease on December eight of this year and for T. D. T. On March 30th of next year with global regulatory reviews also underway in Europe, and the U K phase III pivotal trial Readouts in early 'twenty 'twenty four from <unk>. Both our vans, a catheter triple in CF and our VX five for a program in acute pain. The phase two trial read out by year end 'twenty 'twenty suite from our VX five for a trial in diabetic peripheral neuropathy and completion of enrollment in the phase two portion of the VX 147 phase two sweet program in a M. Kt later this year with that overview, let me now turn to our pipeline update.

We are delivering on our marketed medicines and CF, while simultaneously preparing for commercial excellence in multiple areas ahead of a potential near term launches.

<unk> extra south in both severe sickle cell disease, and transfusion dependent beta thalassemia VX.

VX 548 for acute pain and longer term in peripheral neuropathic pain, and our vans captor triple combination therapy for cystic fibrosis.

Reshma Kewalramani: Most notably we are tracking towards an exa-cel PDUFA date for sickle cell disease on December 8th of this year and for TDT on March 30th of next year with global regulatory reviews also underway in Europe and the UK, Phase III pivotal trial readouts in early 2024 from both our Vanzacaftor triple in CF and our VX-548 program in acute pain. The phase two trial read out by year end 'twenty 'twenty suite from our VX five for a trial in diabetic peripheral neuropathy and completion of enrollment in the phase two portion of the VX 147 phase two sweet program in a M. Kt later this year with that overview, let me now turn to our pipeline update.

Most notably we are tracking towards an extra salt producer date for sickle cell disease on December eight of this year and for T. D. T. On March 30th of next year with global regulatory reviews also underway in Europe, and the U K phase III pivotal trial Readouts in early 'twenty 'twenty four from <unk>.

Both our vans, a catheter triple in CF and our VX five for a program in acute pain.

Reshma Kewalramani: A Phase II trial read out by year end 2023 from our VX-548 trial in diabetic peripheral neuropathy and completion of enrollment in the Phase II portion of the VX-147 Phase 2/3 program in AMKD later this year, with that overview let me now turn to our pipeline update, starting with cystic fibrosis. Next in class vans, a catheter triple combination therapy, we remain on track to complete all three phase III studies Skyline 102, and 103 in patients ages 12 years and above and the Ridge line study in patients ages six to 11 by the end of 2023 and share results from. These three pivotal studies in early 'twenty 'twenty four we have high expectations that the vans. The captor triple combination can deliver greater improvements in C. FTR function than try CAFTA based upon the totality of evidence generated to date, including in vitro from our H B E. S. A's. In phase II studies, the vans the captor Triple holds the potential for enhanced clinical benefit versus truck Kafka for patients. And the convenience of once daily dosing. It also carries a substantially lower royalty burden. In addition, we continue to make progress with another important program in our CF portfolio VX five two to our C. F. T. R mrna therapy in development with our partners that Madonna for more than 5000, and CF patients who cannot benefit from C. F. T. Our modulators, we continue to expect to complete the single ascending dose. <unk> portion and initiate the multiple ascending dose portion of this study by the end of the year, turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

The phase two trial read out by year end 'twenty 'twenty suite from our VX five for a trial in diabetic peripheral neuropathy and completion of enrollment in the phase two portion of the VX 147 phase two sweet program in a M. Kt later this year with that overview, let me now turn to our pipeline update.

Reshma Kewalramani: For our next in class Vanzacaftor triple combination therapy, we remain on track to complete all three Phase III studies SKYLINE 102, and 103 in patients ages 12 years and above and the RIDGELINE study, in patients ages 6 to 11 by the end of 2023 and share results from these three pivotal studies in early 2024. we have high expectations that the vans. The captor triple combination can deliver greater improvements in C. FTR function than try CAFTA based upon the totality of evidence generated to date, including in vitro from our H B E. S. A's. In phase II studies, the vans the captor Triple holds the potential for enhanced clinical benefit versus truck Kafka for patients. And the convenience of once daily dosing. It also carries a substantially lower royalty burden. In addition, we continue to make progress with another important program in our CF portfolio VX five two to our C. F. T. R mrna therapy in development with our partners that Madonna for more than 5000, and CF patients who cannot benefit from C. F. T. Our modulators, we continue to expect to complete the single ascending dose. <unk> portion and initiate the multiple ascending dose portion of this study by the end of the year, turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

Starting with cystic fibrosis.

Next in class vans, a catheter triple combination therapy, we remain on track to complete all three phase III studies Skyline 102, and 103 in patients ages 12 years and above and the Ridge line study in patients ages six to 11 by the end of 2023 and share results from.

Reshma Kewalramani: We have high expectations that the Vanzacaftor triple combination can deliver greater improvements in CFTR function than Trikafta based upon the totality of evidence generated to date, including in vitro from our HBE essays and in phase II studies, the Vanzacaftor riple holds the potential for enhanced clinical benefit versus Trikafta for patients and the convenience of once daily dosing. It also carries a substantially lower royalty burden. In addition, we continue to make progress with another important program in our CF portfolio VX five two to our C. F. T. R mrna therapy in development with our partners that Madonna for more than 5000, and CF patients who cannot benefit from C. F. T. Our modulators, we continue to expect to complete the single ascending dose. <unk> portion and initiate the multiple ascending dose portion of this study by the end of the year, turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

These three pivotal studies in early 'twenty 'twenty four we have high expectations that the vans. The captor triple combination can deliver greater improvements in C. FTR function than try CAFTA based upon the totality of evidence generated to date, including in vitro from our H B E. S. A's.

In phase II studies, the vans the captor Triple holds the potential for enhanced clinical benefit versus truck Kafka for patients.

Reshma Kewalramani: It also carries a substantially lower royalty burden. In addition, we continue to make progress with another important program in our CF portfolio VX five two to our C. F. T. R mrna therapy in development with our partners that Madonna for more than 5000, and CF patients who cannot benefit from C. F. T. Our modulators, we continue to expect to complete the single ascending dose. <unk> portion and initiate the multiple ascending dose portion of this study by the end of the year, turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

Reshma Kewalramani: It also carries a substantially lower royalty burden.

Reshma Kewalramani: In addition, we continue to make progress with another important program in our CF portfolio, VX-522 our CFTR mRNA therapy in development with our partners at Moderna, for the more than 5,000 CF patients who cannot benefit from CFTR modulators, we continue to expect to complete the single ascending dose portion and initiate the multiple ascending dose portion of this study by the end of the year. turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

And the convenience of once daily dosing. It also carries a substantially lower royalty burden.

In addition, we continue to make progress with another important program in our CF portfolio VX five two to our C. F. T. R mrna therapy in development with our partners that Madonna for more than 5000, and CF patients who cannot benefit from C. F. T. Our modulators, we continue to expect to complete the single ascending dose.

<unk> portion and initiate the multiple ascending dose portion of this study by the end of the year, turning now to exercise our CRISPR Cas nine based gene editing program for sickle cell disease, and transfusion dependent beta thalassemia. This program holds the potential to be a one time functional cure for these debilitating.

Reshma Kewalramani: Turning now to Exa-cel, our CRISPR-Cas9 based gene-editing program for sickle cell disease and transfusion dependent beta thalassemia, this program holds the potential to be a one time functional cure for these debilitating and life shortening diseases, Exa-cel represents an enormous advancement for the estimated 32,000 people living with severe sickle cell disease, and transfusion dependent beta thalassemia across the US and Europe. It is a large commercial opportunity on the regulatory front in the U S. We were very pleased to have had the chance to discuss the extra sell filing with members of the FDA Advisory Committee last week and to hear the very compelling stories from patients. The meeting represented a significant milestone for vertex and the first potential CRISPR Cas nine based therapeutics, we look forward to our upcoming <unk> date. And to the potential of bringing this precise durable gene editing therapy to patients. Internationally in both the UK and the EU. We are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months. In addition, we recently submitted a marketing authorization application for Axa cell to the Saudi food and drug authority. Already or S. F D. A I am pleased to share that extra cell is the first medicine ever to receive breakthrough designation by the S. F D. A reflecting both the high unmet need and the high enthusiasm for Axa cell in the Kingdom of Saudi Arabia, We look forward to updating you in the car. Meaning months moving. Moving on to the pain program and VX 548, our novel highly selective Nab 1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see.

Aiding and life shortening diseases extra sell represents an enormous advancement for the estimated 32000 people living with severe sickle cell disease, and transfusion dependent beta thalassemia across the U S and Europe. It is a large commercial opportunity on the regulatory front in the U S.

Reshma Kewalramani: It is a large commercial opportunity. On the regulatory front in the U S. We were very pleased to have had the chance to discuss the extra sell filing with members of the FDA Advisory Committee last week and to hear the very compelling stories from patients. The meeting represented a significant milestone for vertex and the first potential CRISPR Cas nine based therapeutics, we look forward to our upcoming <unk> date. And to the potential of bringing this precise durable gene editing therapy to patients. Internationally in both the UK and the EU. We are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months. In addition, we recently submitted a marketing authorization application for Axa cell to the Saudi food and drug authority. Already or S. F D. A I am pleased to share that extra cell is the first medicine ever to receive breakthrough designation by the S. F D. A reflecting both the high unmet need and the high enthusiasm for Axa cell in the Kingdom of Saudi Arabia, We look forward to updating you in the car. Meaning months moving. Moving on to the pain program and VX 548, our novel highly selective Nab 1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see.

Reshma Kewalramani: It is a large commercial opportunity.

Reshma Kewalramani: On the regulatory front in the US, we were very pleased to have had the chance to discuss the Exa-cel filing with members of the FDA Advisory Committee last week and to hear the very compelling stories from patients, the meeting represented a significant milestone for Vertex and the first potential CRISPR-Cas9 based therapeutics, we look forward to our upcoming PDUFA date and to the potential of bringing this precise, durable gene-editing therapy to patients. Internationally in both the UK and the EU. We are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months. In addition, we recently submitted a marketing authorization application for Axa cell to the Saudi food and drug authority. Already or S. F D. A I am pleased to share that extra cell is the first medicine ever to receive breakthrough designation by the S. F D. A reflecting both the high unmet need and the high enthusiasm for Axa cell in the Kingdom of Saudi Arabia, We look forward to updating you in the car. Meaning months moving. Moving on to the pain program and VX 548, our novel highly selective Nab 1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see.

We were very pleased to have had the chance to discuss the extra sell filing with members of the FDA Advisory Committee last week and to hear the very compelling stories from patients. The meeting represented a significant milestone for vertex and the first potential CRISPR Cas nine based therapeutics, we look forward to our upcoming <unk> date.

And to the potential of bringing this precise durable gene editing therapy to patients.

Reshma Kewalramani: Internationally in both the UK and the EU. We are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months. In addition, we recently submitted a marketing authorization application for Axa cell to the Saudi food and drug authority. Already or S. F D. A I am pleased to share that extra cell is the first medicine ever to receive breakthrough designation by the S. F D. A reflecting both the high unmet need and the high enthusiasm for Axa cell in the Kingdom of Saudi Arabia, We look forward to updating you in the car. Meaning months moving. Moving on to the pain program and VX 548, our novel highly selective Nab 1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see.

Reshma Kewalramani: Internationally in both the UK and the EU we are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months, in addition, we recently submitted a marketing authorization application for Exa-cel to the Saudi Food and Drug Authority or SFDA, I am pleased to share that Exa-cel is the first medicine ever to receive breakthrough designation by the SFDA, reflecting both the high unmet need and the high enthusiasm for Exa-cel in the Kingdom of Saudi Arabia, we look forward to updating you in the coming months.

Internationally in both the UK and the EU. We are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months. In addition, we recently submitted a marketing authorization application for Axa cell to the Saudi food and drug authority.

Already or S. F D. A I am pleased to share that extra cell is the first medicine ever to receive breakthrough designation by the S. F D. A reflecting both the high unmet need and the high enthusiasm for Axa cell in the Kingdom of Saudi Arabia, We look forward to updating you in the car.

Reshma Kewalramani: Moving on to the pain program and VX-548, our novel highly selective NaV1.8 inhibitor that holds the promise for effective pain relief, without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see. <unk> arms safety and efficacy study remain on track to complete by the end of this year as previously discussed we will unwind analyze and share results on all three studies at the same time and we expect to do so in early 'twenty 'twenty four. This comprehensive phase III program has been designed to support a broad moderate to severe acute pain label and to enable prescribing and usage across multiple care settings. We're also studying the X FIFO rate in peripheral neuropathic pain or P. N P. Yet another area of high unmet need recall, we pre. Obviously demonstrated positive proof of concept with the predecessor molecule VX 150 in neuropathic pain in diabetic peripheral neuropathy or D. P. N. I am pleased to share that we have completed our phase II 12 week dose ranging proof of concept study, we anticipate sharing the results. From this phase two trial by the end of this year as we await the D. P. N results. We're excited to initiate a second phase two peripheral neuropathic pain study of VX 548 by the end of the year in lumbosacral Radiculopathy or L. S. R. It's a type of neuropathic pain. Caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

Meaning months moving.

Moving on to the pain program and VX 548, our novel highly selective Nab 1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids, and therefore represents a significant commercial opportunity in both acute and neuropathic pain.

Reshma Kewalramani: The pace of the Phase III program in acute pain has been rapid, which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious, non-opioid acute pain therapy, we have completed the randomized control trial in abdominoplasty, the RCT in Bunionectomy and a single arm safety and efficacy study remain on track to complete by the end of this year, as previously discussed we will unwind analyze and share results on all three studies at the same time and we expect to do so in early 'twenty 'twenty four. This comprehensive phase III program has been designed to support a broad moderate to severe acute pain label and to enable prescribing and usage across multiple care settings. We're also studying the X FIFO rate in peripheral neuropathic pain or P. N P. Yet another area of high unmet need recall, we pre. Obviously demonstrated positive proof of concept with the predecessor molecule VX 150 in neuropathic pain in diabetic peripheral neuropathy or D. P. N. I am pleased to share that we have completed our phase II 12 week dose ranging proof of concept study, we anticipate sharing the results. From this phase two trial by the end of this year as we await the D. P. N results. We're excited to initiate a second phase two peripheral neuropathic pain study of VX 548 by the end of the year in lumbosacral Radiculopathy or L. S. R. It's a type of neuropathic pain. Caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

The pace of the phase III program in acute pain has been rapid which we see as an indication of the high unmet need and strong patient and physician interest in an efficacious non opioid acute pain therapy. We've completed the randomized control trial in abdominal plasty the RCT in Bunionectomy Andi see.

<unk> arms safety and efficacy study remain on track to complete by the end of this year as previously discussed we will unwind analyze and share results on all three studies at the same time and we expect to do so in early 'twenty 'twenty four.

Reshma Kewalramani: As previously discussed we will unblind, analyze and share results on all three studies at the same time and we expect to do so in early 2024, this comprehensive Phase III program has been designed to support a broad, moderate to severe acute pain label and to enable prescribing and usage across multiple care settings. We're also studying the X FIFO rate in peripheral neuropathic pain or P. N P. Yet another area of high unmet need recall, we pre. Obviously demonstrated positive proof of concept with the predecessor molecule VX 150 in neuropathic pain in diabetic peripheral neuropathy or D. P. N. I am pleased to share that we have completed our phase II 12 week dose ranging proof of concept study, we anticipate sharing the results. From this phase two trial by the end of this year as we await the D. P. N results. We're excited to initiate a second phase two peripheral neuropathic pain study of VX 548 by the end of the year in lumbosacral Radiculopathy or L. S. R. It's a type of neuropathic pain. Caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

This comprehensive phase III program has been designed to support a broad moderate to severe acute pain label and to enable prescribing and usage across multiple care settings. We're also studying the X FIFO rate in peripheral neuropathic pain or P. N P. Yet another area of high unmet need recall, we pre.

Reshma Kewalramani: We're also studying VX-548 in peripheral neuropathic pain or PNP, Yet another area of high unmet need recall, we previously demonstrated positive proof of concept with the predecessor molecule VX-150 in neuropathic pain, in diabetic peripheral neuropathy or DPN, I am pleased to share that we have completed our Phase II, 12 week, dose ranging proof of concept study, we anticipate sharing the results. From this phase two trial by the end of this year as we await the D. P. N results. We're excited to initiate a second phase two peripheral neuropathic pain study of VX 548 by the end of the year in lumbosacral Radiculopathy or L. S. R. It's a type of neuropathic pain. Caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

Obviously demonstrated positive proof of concept with the predecessor molecule VX 150 in neuropathic pain in diabetic peripheral neuropathy or D. P. N. I am pleased to share that we have completed our phase II 12 week dose ranging proof of concept study, we anticipate sharing the results.

Reshma Kewalramani: We anticipate sharing the results from this Phase II trial by the end of this year, as we await the DPN results, we're excited to initiate a second, Phase II, peripheral neuropathic pain study of VX-548 by the end of the year in Lumbosacral Radiculopathy or LSR, it's a type of neuropathic pain caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

From this phase two trial by the end of this year as we await the D. P. N results. We're excited to initiate a second phase two peripheral neuropathic pain study of VX 548 by the end of the year in lumbosacral Radiculopathy or L. S. R. It's a type of neuropathic pain.

Reshma Kewalramani: it's a type of neuropathic pain caused by the impairment of nerve routes in the area of the lumbar spine give. Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types. Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

Reshma Kewalramani: It's a type of neuropathic pain caused by the impairment of nerve routes in the area of the lumbar spine, given the limited therapeutic options, the significant opportunity to serve a large number of patients and the promise that the NaV1.8 mechanism holds, we are excited to pursue the potential of VX-548 in each of these neuropathic pain types.

Caused by the impairment of nerve routes in the area of the lumbar spine give.

Given the limited therapeutic options the significant opportunity to serve a large number of patients and the promise that the Nab 1.8 mechanism holds we are excited to pursue the potential of VX 548 in each of these neuropathic pain types.

Reshma Kewalramani: Next onto type 1 diabetes, where we are evaluating stem-cell-derived, fully differentiated, insulin producing islet cells for people with type 1 diabetes, our goal is to develop a potential, one time, functional cure for the millions of people living with type one diabetes, including the more than 2.5 million patients in North America, and Europe alone. The VX 880, or naked cell program, where we've already established proof of concept is foundational. Two the type one diabetes program as a whole here patients take standard immunosuppressants to protect the islet cells from the immune system. E I S. T last month, we presented positive updated clinical data from all patients in parts, a and B of the VX 880 study with regard to study status part C of the study, which administers the full target dose with concurrent dosing is now fully enrolled. Our second program VX 264, or the South plus device program encapsulates the same cells in a proprietary immuno protective device and hence there is no requirement for Immunosuppressants, we have begun enrollment and dosing in part a of the VX two six for study. And finally, our third program still under research stage is our hyper immune cells in which we added the same fully differentiate itself so as to obviate the need for Immunosuppressants. Transitioning now to an axa planar VX 147, the first potential medicine to target the underlying cause of April while one mediated kidney disease or a M. K D. D knocks the planned pivotal program for patients with a M. K D is a single adaptive phase two three study with a pathway to accelerated approval in. The U S. The phase two b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to phase three of the study in Q1 of 'twenty 'twenty four. Now turning to Alpha one antitrypsin deficiency or a a T D.

Next onto type one diabetes, where we are evaluating stem cell derived fully differentiated insulin producing islet cells for people with type one diabetes.

Our goal is to develop a potential one time functional cure for the millions of people living with type one diabetes, including the more than 2.5 million patients in North America, and Europe alone. The VX 880, or naked cell program, where we've already established proof of concept is foundational.

Reshma Kewalramani: The VX-880, or naked cell program, where we've already established proof of concept, is foundational to the type 1 diabetes program as a whole, here patients take standard immunosuppressants to protect the islet cells from the immune system, at EASD last month, we presented positive updated clinical data from all patients in parts, A and B of the VX-880 study. with regard to study status part C of the study, which administers the full target dose with concurrent dosing is now fully enrolled. Our second program VX 264, or the South plus device program encapsulates the same cells in a proprietary immuno protective device and hence there is no requirement for Immunosuppressants, we have begun enrollment and dosing in part a of the VX two six for study. And finally, our third program still under research stage is our hyper immune cells in which we added the same fully differentiate itself so as to obviate the need for Immunosuppressants. Transitioning now to an axa planar VX 147, the first potential medicine to target the underlying cause of April while one mediated kidney disease or a M. K D. D knocks the planned pivotal program for patients with a M. K D is a single adaptive phase two three study with a pathway to accelerated approval in. The U S. The phase two b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to phase three of the study in Q1 of 'twenty 'twenty four. Now turning to Alpha one antitrypsin deficiency or a a T D.

Two the type one diabetes program as a whole here patients take standard immunosuppressants to protect the islet cells from the immune system.

E I S. T last month, we presented positive updated clinical data from all patients in parts, a and B of the VX 880 study with regard to study status part C of the study, which administers the full target dose with concurrent dosing is now fully enrolled.

Reshma Kewalramani: With regard to study status, part C of the study, which administers the full target dose with concurrent dosing is now fully enrolled, our second program VX-264, or the cells + device program, encapsulates the same cells in a proprietary immuno protective device and hence, there is no requirement for Immunosuppressants, we have begun enrollment and dosing in part A of the VX-264 study. And finally, our third program still under research stage is our hyper immune cells in which we added the same fully differentiate itself so as to obviate the need for Immunosuppressants. Transitioning now to an axa planar VX 147, the first potential medicine to target the underlying cause of April while one mediated kidney disease or a M. K D. D knocks the planned pivotal program for patients with a M. K D is a single adaptive phase two three study with a pathway to accelerated approval in. The U S. The phase two b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to phase three of the study in Q1 of 'twenty 'twenty four. Now turning to Alpha one antitrypsin deficiency or a a T D.

Our second program VX 264, or the South plus device program encapsulates the same cells in a proprietary immuno protective device and hence there is no requirement for Immunosuppressants, we have begun enrollment and dosing in part a of the VX two six for study.

Reshma Kewalramani: And finally, our third program, still under research stage is our hypoimmune cells, in which we added the same fully differentiate cells so as to obviate the need for Immunosuppressants, transitioning now to Inaxaplin VX 147, the first potential medicine to target the underlying cause of April while one mediated kidney disease or a M. K D. D knocks the planned pivotal program for patients with a M. K D is a single adaptive phase two three study with a pathway to accelerated approval in. The U S. The phase two b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to phase three of the study in Q1 of 'twenty 'twenty four. Now turning to Alpha one antitrypsin deficiency or a a T D.

And finally, our third program still under research stage is our hyper immune cells in which we added the same fully differentiate itself so as to obviate the need for Immunosuppressants.

Reshma Kewalramani: Transitioning now to Inaxaplin or VX-147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease or AMKD, the Inaxaplin pivotal program for patients with AMKD is a single, adaptive Phase 2/3 study with a pathway to accelerated approval in the US, the Phase 2b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to Phase III of the study in Q1 of 2024. Now turning to Alpha one antitrypsin deficiency or a a T D.

Transitioning now to an axa planar VX 147, the first potential medicine to target the underlying cause of April while one mediated kidney disease or a M. K D. D knocks the planned pivotal program for patients with a M. K D is a single adaptive phase two three study with a pathway to accelerated approval in.

The U S.

The phase two b dose ranging portion of the study continues to enroll and dose patients and we expect to complete enrollment by the end of this year, we now expect to select a dose and move to phase three of the study in Q1 of 'twenty 'twenty four.

Reshma Kewalramani: Now turning to Alpha-1 antitrypsin deficiency or AATD, we have discontinued development of VX-864 due to non-serious rash events in some patients in the Phase II program, our next generation molecules VX-634, and VX-668, both have greater potency and better drug-like properties and are both in Phase I clinical trials, these trials continue to enroll and dose healthy volunteers, we look forward to sharing more on AATD, including next steps as we learn more in the coming months, with that I'll turn it over to Stuart Thanks.

Now turning to Alpha one antitrypsin deficiency or a a T D.

We have discontinued development of VX 864, due to non serious rash events in some patients in the phase two program. Our next generation molecules VX 634, and VX 668, both have greater potency and better drug like properties and are both in fee.

As one clinical trials.

These trials continue to enroll and dose healthy volunteers, we look forward to sharing more on a a T D, including next steps as we learn more in the coming months.

With that I'll turn it over to Stuart Thanks.

Stuart Arbuckle: Thanks Reshma, I will focus my remarks tonight on CF, Exa-cel and Pain, we delivered strong third quarter commercial results with CF product revenue growing 6% globally versus the prior year, as we continued to reach patients in younger age groups as a result of new regulatory approvals and via new reimbursement agreements. Our strategy in CF has always been to develop medicines for all people living with CF and to serially innovate to deliver increased clinical benefit. We will continue to execute near term with a focus on younger age groups and then our goal is to drive growth over the medium term with the vans are capped a triple combination and longer term with our mrna program VX 522 that we are developing in partnership with Madonna. Now turning to X yourself. Our next targeted launch and potential multibillion dollar opportunity. This quarter I will provide some insights as to launch readiness ahead of potential near term regulatory approvals and then detail the patient journey in the U S and Europe. We've previously highlighted that there are approximately 32000 eligible patients with severe disease 25000, with sickle cell disease, and 7000 with beta thal. Alice EMEA the majority of sickle cell disease patients are in the U S. While the majority of T. D. T patients are in Europe within Europe, approximately 75% of all eligible patients live in four countries. The U K, France, Italy, and Germany, Italy has by far the highest prevalence of eligible T D T patients. While France and the U K represent the majority of eligible patients with sickle cell disease in the U S and Europe. We are on track with our globally enables supply network and launch preparations with authorized treatment centers and payers. Including our recently completed application for a new technology add on payment or <unk> and tap for Medicare patients in the U S. In addition, Rushmore mentioned, our extra sell MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law.

Stuart Arbuckle: Our strategy in CF has always been to develop medicines for all people living with CF and to serially innovate to deliver increased clinical benefit, we will continue to execute near term with a focus on younger age groups and then our goal is to drive growth over the medium term with the Vanzacaftor triple combination and longer term with our mRNA program VX-522 that we are developing in partnership with Moderna. Now turning to X yourself. Our next targeted launch and potential multibillion dollar opportunity. This quarter I will provide some insights as to launch readiness ahead of potential near term regulatory approvals and then detail the patient journey in the U S and Europe. We've previously highlighted that there are approximately 32000 eligible patients with severe disease 25000, with sickle cell disease, and 7000 with beta thal. Alice EMEA the majority of sickle cell disease patients are in the U S. While the majority of T. D. T patients are in Europe within Europe, approximately 75% of all eligible patients live in four countries. The U K, France, Italy, and Germany, Italy has by far the highest prevalence of eligible T D T patients. While France and the U K represent the majority of eligible patients with sickle cell disease in the U S and Europe. We are on track with our globally enables supply network and launch preparations with authorized treatment centers and payers. Including our recently completed application for a new technology add on payment or <unk> and tap for Medicare patients in the U S. In addition, Rushmore mentioned, our extra sell MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law.

Our strategy in CF has always been to develop medicines for all people living with CF and to serially innovate to deliver increased clinical benefit.

We will continue to execute near term with a focus on younger age groups and then our goal is to drive growth over the medium term with the vans are capped a triple combination and longer term with our mrna program VX 522 that we are developing in partnership with Madonna.

Stuart Arbuckle: Now turning to Exa-cel, our next targeted launch and potential multibillion dollar opportunity, this quarter I will provide some insights as to launch readiness ahead of potential near term regulatory approvals and then detail the patient journey, in the U S and Europe, we've previously highlighted that there are approximately 32,000 eligible patients with severe disease, 25,000 with sickle cell disease and 7000 with Beta thalassemia. the majority of sickle cell disease patients are in the U S. While the majority of T. D. T patients are in Europe within Europe, approximately 75% of all eligible patients live in four countries. The U K, France, Italy, and Germany, Italy has by far the highest prevalence of eligible T D T patients. While France and the U K represent the majority of eligible patients with sickle cell disease in the U S and Europe. We are on track with our globally enables supply network and launch preparations with authorized treatment centers and payers. Including our recently completed application for a new technology add on payment or <unk> and tap for Medicare patients in the U S. In addition, Rushmore mentioned, our extra sell MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law.

Now turning to X yourself.

Our next targeted launch and potential multibillion dollar opportunity.

This quarter I will provide some insights as to launch readiness ahead of potential near term regulatory approvals and then detail the patient journey in the U S and Europe. We've previously highlighted that there are approximately 32000 eligible patients with severe disease 25000, with sickle cell disease, and 7000 with beta thal.

Stuart Arbuckle: The majority of sickle cell disease patients are in the US While the majority of TDT patients are in Europe, within Europe, approximately 75% of all eligible patients live in four countries, the UK, France, Italy, and Germany, Italy has by far the highest prevalence of eligible TDT patients, while France and the UK represent the majority of eligible patients with sickle cell disease. in the U S and Europe. We are on track with our globally enables supply network and launch preparations with authorized treatment centers and payers. Including our recently completed application for a new technology add on payment or <unk> and tap for Medicare patients in the U S. In addition, Rushmore mentioned, our extra sell MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law.

Alice EMEA the majority of sickle cell disease patients are in the U S. While the majority of T. D. T patients are in Europe within Europe, approximately 75% of all eligible patients live in four countries. The U K, France, Italy, and Germany, Italy has by far the highest prevalence of eligible T D T patients.

While France and the U K represent the majority of eligible patients with sickle cell disease in the U S and Europe. We are on track with our globally enables supply network and launch preparations with authorized treatment centers and payers.

Stuart Arbuckle: In the US and Europe, we are on track with our globally-enabled supply network and launch preparations with authorized treatment centers and payers, including our recently completed application for a new technology add-on payment or NTAP for Medicare patients in the US. In addition, Rushmore mentioned, our Exa-cel MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law. Forward to providing you with more information on future calls about this important additional opportunity as we prepare for approval and launch it is important to understand the extra cell patient journey, which can be broken down into three key phases, each of which can take several months first pre treatment initially when a potential extra self pay. <unk> and their Hematologists decided the therapy is right for them. The patient is then referred to a transplant physician at an a T. C. Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell second cell collection in manufacturing. This phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis. The patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization. And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

Including our recently completed application for a new technology add on payment or <unk> and tap for Medicare patients in the U S.

Stuart Arbuckle: In addition, Reshma mentioned our exa-cel MAA submission in the Kingdom of Saudi Arabia or KSA, our team is engaging with the Saudi Health authorities and working on the processes to support ATC activation, access and reimbursement with the aim of bringing Exa-cel to the thousands of patients with severe disease in KSA, we look forward to providing you with more information on future calls about this important additional opportunity. As we prepare for approval and launch it is important to understand the extra cell patient journey, which can be broken down into three key phases, each of which can take several months first pre treatment initially when a potential extra self pay. <unk> and their Hematologists decided the therapy is right for them. The patient is then referred to a transplant physician at an a T. C. Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell second cell collection in manufacturing. This phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis. The patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization. And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

In addition, Rushmore mentioned, our extra sell MAA submission in the Kingdom of Saudi Arabia. Okay S. A our team is engaging with the Saudi health authorities and working on the processes to support a T C activation access and reimbursement with the aim of bringing extra sell to the thousands of patients with severe disease in KSA we law.

Forward to providing you with more information on future calls about this important additional opportunity as we prepare for approval and launch it is important to understand the extra cell patient journey, which can be broken down into three key phases, each of which can take several months first pre treatment initially when a potential extra self pay.

Stuart Arbuckle: As we prepare for approval and launch, it is important to understand the Exa-cel patient journey, which can be broken down into three key phases, each of which can take several months, first pre-treatment, initially when a potential Exa-cel patient and their Hematologists decide the therapy is right for them, the patient is then referred to a transplant physician at an ATC. Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell second cell collection in manufacturing. This phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis. The patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization. And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

<unk> and their Hematologists decided the therapy is right for them. The patient is then referred to a transplant physician at an a T. C. Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell second cell collection in manufacturing.

Stuart Arbuckle: Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell, second cell collection in manufacturing, this phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis. The patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization. And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

Stuart Arbuckle: Once that referral is scheduled the patient then undergoes a full workup to determine whether they are fit for treatment with extra cell,

Stuart Arbuckle: Second cell collection and manufacturing, this phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis, the patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization. And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

This phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through a pheresis.

The patient cells are then sent to our manufacturing facilities, where they are edited and then tested for quality control.

Cell collection takes longer for sickle cell disease patients given the need for two months of Red blood cell transfusions prior to mobilization.

Stuart Arbuckle: Cell collection takes longer for sickle cell disease patients, given the need for two months of Red blood cell transfusions prior to mobilization and ,on average, two rounds of mobilization and apheresis, in contrast TDT patients do not require pre-mobilization transfusions and typically only require one round of mobilization and apheresis. The final phase is treatment once the edited cells already the patient starts the treatment phase, which includes Milo ablative conditioning infusion of the edited cells at which point, we will recognize revenue for the therapy, and then waiting for an grafman and post infusion care.

And on average two rounds of mobilization and a pheresis in contrast T. D. T patients do not require pre mobilization transfusions and typically only require one round of mobilization and apheresis.

Stuart Arbuckle: The final phase is treatment, once the edited cells are ready the patient starts the treatment phase, which includes Myeloablative conditioning, infusion of the edited cells, at which point we will recognize revenue for the therapy and then waiting for engraftment and post-infusion care. Critical time and factor in this phase is the patient's preferred timing for treatment. As they must choose a time that works best for their lives given this step involves an approximate one month hospital stay. This patient journey is consistent across all geographies given the multiple steps in the duration of the journey, we expect 2024 to be a foundational year for extra cell as the first patients begin this journey and vertex works to deliver transformative patient outcomes with the possibility of a lifetime of benefit shifting now to VX five. For rate are highly selective NAV 1.8 inhibits F a pain. Given the programs rapid pace of clinical advancement, we have developed our go to market strategies and are actively planning for a potential near term launch I'd like to share an outline of some of the work we've done to size each market opportunity overall, the pain opportunity is massive in the U S alone each year more than 90 million patients are treated for. For acute or peripheral neuropathic pain, both acute N P. N P. R. Each multibillion dollar markets today. Despite the fact that essentially all prescriptions are generic and we see additional upside to these opportunities given the challenges of currently approved treatments the unmet need in pain stems from the sub optimal benefit risk profiles of <unk>. Existing agents such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gaba pension odds prescribed for neuropathic pain, we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute.

The final phase is treatment once the edited cells already the patient starts the treatment phase, which includes Milo ablative conditioning infusion of the edited cells at which point, we will recognize revenue for the therapy, and then waiting for an grafman and post infusion care.

Critical time and factor in this phase is the patient's preferred timing for treatment.

As they must choose a time that works best for their lives given this step involves an approximate one month hospital stay.

Stuart Arbuckle: This patient journey is consistent across all geographies, given the multiple steps and the duration of the journey, we expect 2024 to be a foundational year for Exa-cel, as the first patients begin this journey and Vertex works to deliver transformative patient outcomes with the possibility of a lifetime of benefit. shifting now to VX five. For rate are highly selective NAV 1.8 inhibits F a pain. Given the programs rapid pace of clinical advancement, we have developed our go to market strategies and are actively planning for a potential near term launch I'd like to share an outline of some of the work we've done to size each market opportunity overall, the pain opportunity is massive in the U S alone each year more than 90 million patients are treated for. For acute or peripheral neuropathic pain, both acute N P. N P. R. Each multibillion dollar markets today. Despite the fact that essentially all prescriptions are generic and we see additional upside to these opportunities given the challenges of currently approved treatments the unmet need in pain stems from the sub optimal benefit risk profiles of <unk>. Existing agents such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gaba pension odds prescribed for neuropathic pain, we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute.

This patient journey is consistent across all geographies given the multiple steps in the duration of the journey, we expect 2024 to be a foundational year for extra cell as the first patients begin this journey and vertex works to deliver transformative patient outcomes with the possibility of a lifetime of benefit shifting now to VX five.

Stuart Arbuckle: Shifting now to VX-548, our highly selective NaV1.8 inhibitor for pain, given the programs rapid pace of clinical advancement, we have developed our go to market strategies and are actively planning for a potential near term launch, I'd like to share an outline of some of the work we've done to size each market opportunity. overall, the pain opportunity is massive in the U S alone each year more than 90 million patients are treated for. For acute or peripheral neuropathic pain, both acute N P. N P. R. Each multibillion dollar markets today. Despite the fact that essentially all prescriptions are generic and we see additional upside to these opportunities given the challenges of currently approved treatments the unmet need in pain stems from the sub optimal benefit risk profiles of <unk>. Existing agents such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gaba pension odds prescribed for neuropathic pain, we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute.

For rate are highly selective NAV 1.8 inhibits F a pain.

Given the programs rapid pace of clinical advancement, we have developed our go to market strategies and are actively planning for a potential near term launch I'd like to share an outline of some of the work we've done to size each market opportunity overall, the pain opportunity is massive in the U S alone each year more than 90 million patients are treated for.

Stuart Arbuckle: Overall, the pain opportunity is massive, in the US alone each year more than 90 million patients are treated for acute or peripheral neuropathic pain, both acute and PNP are each multibillion dollar markets today, despite the fact that essentially all prescriptions are generic and we see additional upside to these opportunities given the challenges of currently approved treatments the unmet need in pain stems from the sub optimal benefit risk profiles of <unk>. Existing agents such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gaba pension odds prescribed for neuropathic pain, we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute.

For acute or peripheral neuropathic pain, both acute N P. N P. R. Each multibillion dollar markets today. Despite the fact that essentially all prescriptions are generic and we see additional upside to these opportunities given the challenges of currently approved treatments the unmet need in pain stems from the sub optimal benefit risk profiles of <unk>.

Stuart Arbuckle: The unmet need in pain stems from the sub-optimal benefit risk profiles of existing agents, such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gabapentinoids prescribed for neuropathic pain. we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute. Pain, we estimate approximately 80 million patients are prescribed medicine for their moderate to severe acute pain every year in the U S more than two thirds of patients receive acute pain treatment driven by an institution either during a hospital or ambulatory surgery center visit or at discharge as hospital driven prescribing is concentrated amongst them. 2000 hospitals, and 200 idea and we can reach a large proportion of the patient opportunity with a specialty sales force as Rushmore mentioned, the peripheral neuropathy pain study in D. P. N is completed and the L. S. Off study is about to begin P. N. P is an exciting commercial opportunity given that approximately 10 million. Patients are prescribed the medicine for a P. N P condition every year in the U S with chronic dosing, but limited treatment options P. N P fits all vertex specialty model perfectly P. N. P is a collection of chronic conditions in which nerve and payment causes pain D. P N and L. S are two of the largest patient segments. <unk> L. S. All represents over 40% of all P. N P patients while D. P. N represents approximately 20% of all P. N P patients <unk>. Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there. Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

Existing agents such as the adverse effects in addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the Gaba pension odds prescribed for neuropathic pain, we believe the innovation of VX 548, and its overall profile could provide a transformative auction for millions of patients in acute.

Stuart Arbuckle: We believe the innovation of VX-548, and its overall profile could provide a transformative option for millions of patients, in acute pain, we estimate approximately 80 million patients are prescribed medicines for their moderate to severe acute pain every year in the US more than two thirds of patients receive acute pain treatment driven by an institution either during a hospital or ambulatory surgery center visit or at discharge as hospital driven prescribing is concentrated amongst them. 2000 hospitals, and 200 idea and we can reach a large proportion of the patient opportunity with a specialty sales force as Rushmore mentioned, the peripheral neuropathy pain study in D. P. N is completed and the L. S. Off study is about to begin P. N. P is an exciting commercial opportunity given that approximately 10 million. Patients are prescribed the medicine for a P. N P condition every year in the U S with chronic dosing, but limited treatment options P. N P fits all vertex specialty model perfectly P. N. P is a collection of chronic conditions in which nerve and payment causes pain D. P N and L. S are two of the largest patient segments. <unk> L. S. All represents over 40% of all P. N P patients while D. P. N represents approximately 20% of all P. N P patients <unk>. Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there. Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

Pain, we estimate approximately 80 million patients are prescribed medicine for their moderate to severe acute pain every year in the U S more than two thirds of patients receive acute pain treatment driven by an institution either during a hospital or ambulatory surgery center visit or at discharge as hospital driven prescribing is concentrated amongst them.

Stuart Arbuckle: More than two thirds of patients receive acute pain treatment driven by an institution, either during a hospital or ambulatory surgery center visit or at discharge, as hospital-driven prescribing is concentrated amongst some 2,000 hospitals, and 200 IDNs we can reach a large proportion of the patient opportunity with a specialty sales force. as Rushmore mentioned, the peripheral neuropathy pain study in D. P. N is completed and the L. S. Off study is about to begin P. N. P is an exciting commercial opportunity given that approximately 10 million. Patients are prescribed the medicine for a P. N P condition every year in the U S with chronic dosing, but limited treatment options P. N P fits all vertex specialty model perfectly P. N. P is a collection of chronic conditions in which nerve and payment causes pain D. P N and L. S are two of the largest patient segments. <unk> L. S. All represents over 40% of all P. N P patients while D. P. N represents approximately 20% of all P. N P patients <unk>. Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there. Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

2000 hospitals, and 200 idea and we can reach a large proportion of the patient opportunity with a specialty sales force as Rushmore mentioned, the peripheral neuropathy pain study in D. P. N is completed and the L. S. Off study is about to begin P. N. P is an exciting commercial opportunity given that approximately 10 million.

Stuart Arbuckle: As Reshma mentioned, the peripheral neuropathic pain study in DPN is completed and the LSR study is about to begin, PNP is an exciting commercial opportunity, given that approximately 10 million patients are prescribed the medicine for a PNP condition every year in the US with chronic dosing, but limited treatment options P. N P fits all vertex specialty model perfectly P. N. P is a collection of chronic conditions in which nerve and payment causes pain D. P N and L. S are two of the largest patient segments. <unk> L. S. All represents over 40% of all P. N P patients while D. P. N represents approximately 20% of all P. N P patients <unk>. Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there. Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

Patients are prescribed the medicine for a P. N P condition every year in the U S with chronic dosing, but limited treatment options P. N P fits all vertex specialty model perfectly P. N. P is a collection of chronic conditions in which nerve and payment causes pain D. P N and L. S are two of the largest patient segments.

Stuart Arbuckle: PNP fits our vertex specialty model perfectly, PNP is a collection of chronic conditions in which nerve impairment causes pain, DPN and LSR are two of the largest patient segments, LSR represents over 40% of all PNP patients while DPN represents approximately 20% of all PNP patients <unk>. Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there. Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

<unk> L. S. All represents over 40% of all P. N P patients while D. P. N represents approximately 20% of all P. N P patients <unk>.

Stuart Arbuckle: Specialists play a critical role in treating PNP, as patients can be on multiple treatments and are often in search of more effective pain control, given the limited therapeutic options, therefore, we believe the PNP segment is addressable with a specialty sales force and we look forward to bringing innovation to PNP patients. In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF. And VX 548 in acute pain. Both of which have the potential to dramatically improve patients' lives and represent significant market opportunities for vertex. I will now turn the call over to Charlie to review the financials.

Specialists play a critical role in treating P. N P. As patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options there.

Therefore, we believe the P. N P segment is addressable with a specialty sales force and we look forward to bringing innovation to P. N P patients.

Stuart Arbuckle: In conclusion, it's an exciting time at Vertex, we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with Exa-cel, we're also preparing for multiple additional near term launches, including the Vanzacaftor triple in CF and VX-548 in acute pain, both of which have the potential to dramatically improve patients' lives and represent significant market opportunities for Vertex. I will now turn the call over to Charlie to review the financials.

In conclusion, it's an exciting time at vertex we continued to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with X S. L. We're also preparing for multiple additional near term launches, including the vans are capped a triple in CF.

And VX 548 in acute pain.

Both of which have the potential to dramatically improve patients' lives and represent significant market opportunities for vertex.

Stuart Arbuckle: I will now turn the call over to Charlie to review the financials.

I will now turn the call over to Charlie to review the financials.

Charles Wagner: Thanks Stuart, Vertex's excellent results in the third quarter of 2023 demonstrate once again our consistent strong performance and attractive growth profile, third quarter 2023 revenue increased 6% year over year to $2.48 billion, US revenue grew 7% year over year following the recent FDA approval of Trikafta in patients ages 2 to 5 and outside the US, revenue grew 6% year over year on continued strong uptake of Trikafta/Kaftrio in markets with recently achieved reimbursement as well as label extensions in younger age groups. as anticipated in Q3, we saw the drawdown of inventory in certain international markets. In contrast to the increases in inventory that we experienced in the first half of the year year to date revenue of 7.35 billion represents 11% growth over the corresponding prior year period, including an approximate 150 basis point headwind from changes in foreign currency overall, the primary drivers of revenue growth in 'twenty two. All three have been in line with our expectations third quarter 'twenty twenty-three combined non-GAAP R&D acquired IP, R&D and SG&A expenses were $993 million compared to $758 million in the third quarter of 'twenty to Q3 'twenty 'twenty. Three results include $52 million of acquired IP R&D charge. <unk> compared to $29 million of such charges in the third quarter of 2020 two. Operating expense growth was driven as expected by continued investment in research and our pipeline throughout 2023 the most significant areas of increased investment versus prior year included the clinical studies for VX 548 in acute pain. The vans the captor triple in CF and for type one diabetes as well as build out of <unk>.

Trey CAFTA in patients ages, two to five and outside the U S revenue grew 6% year over year on continued strong uptake of trade capped a caf trio in markets with recently achieved reimbursement as well as label extensions in younger age groups as anticipated in Q3, we saw the drawdown of inventory in certain international markets.

Charles Wagner: As anticipated in Q3, we saw the drawdown of inventory in certain international markets, in contrast to the increases in inventory that we experienced in the first half of the year, year to date revenue of $7.35 billion represents 11% growth over the corresponding prior year period, including an approximate 150 basis point headwind from changes in foreign currency. overall, the primary drivers of revenue growth in 'twenty two. All three have been in line with our expectations third quarter 'twenty twenty-three combined non-GAAP R&D acquired IP, R&D and SG&A expenses were $993 million compared to $758 million in the third quarter of 'twenty to Q3 'twenty 'twenty. Three results include $52 million of acquired IP R&D charge. <unk> compared to $29 million of such charges in the third quarter of 2020 two. Operating expense growth was driven as expected by continued investment in research and our pipeline throughout 2023 the most significant areas of increased investment versus prior year included the clinical studies for VX 548 in acute pain. The vans the captor triple in CF and for type one diabetes as well as build out of <unk>.

In contrast to the increases in inventory that we experienced in the first half of the year year to date revenue of 7.35 billion represents 11% growth over the corresponding prior year period, including an approximate 150 basis point headwind from changes in foreign currency overall, the primary drivers of revenue growth in 'twenty two.

Charles Wagner: Overall, the primary drivers of revenue growth in 2023 have been in line with our expectations. third quarter 'twenty twenty-three combined non-GAAP R&D acquired IP, R&D and SG&A expenses were $993 million compared to $758 million in the third quarter of 'twenty to Q3 'twenty 'twenty. Three results include $52 million of acquired IP R&D charge. <unk> compared to $29 million of such charges in the third quarter of 2020 two. Operating expense growth was driven as expected by continued investment in research and our pipeline throughout 2023 the most significant areas of increased investment versus prior year included the clinical studies for VX 548 in acute pain. The vans the captor triple in CF and for type one diabetes as well as build out of <unk>.

Charles Wagner: Overall, the primary drivers of revenue growth in 2023 have been in line with our expectations.

All three have been in line with our expectations third quarter 'twenty twenty-three combined non-GAAP R&D acquired IP, R&D and SG&A expenses were $993 million compared to $758 million in the third quarter of 'twenty to Q3 'twenty 'twenty. Three results include $52 million of acquired IP R&D charge.

Charles Wagner: Third quarter 2023 combined non-GAAP R&D acquired IPR&D and SG&A expenses were $993 million, compared to $758 million in the third quarter of '22, Q3 2023 results include $52 million of acquired IPR&D charges, compared to $29 million of such charges in the third quarter of 2020 two. Operating expense growth was driven as expected by continued investment in research and our pipeline throughout 2023 the most significant areas of increased investment versus prior year included the clinical studies for VX 548 in acute pain. The vans the captor triple in CF and for type one diabetes as well as build out of <unk>.

<unk> compared to $29 million of such charges in the third quarter of 2020 two.

Charles Wagner: Operating expense growth was driven, as expected, by continued investment in research and our pipeline, throughout 2023 the most significant areas of increased investment versus prior year, included the clinical studies for VX-548 in acute pain, the Vanzacaftor triple in CF and for type one diabetes as well as build out of capabilities for our expanding pipeline. in. In addition, we continued our pre commercial activities for eggs or cell and other anticipated near term launches third quarter 2023 non-GAAP operating income was 1.17 billion compared to 1.29 billion in the third quarter of 2022. Third quarter 2023, non-GAAP earnings per share were $4.08, representing 2% growth compared to $4.01 in the third quarter of 2022. We ended the quarter with 13.6 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 year to date, we have completed nearly 10 transactions with total consideration of over $500 million. We've also. <unk> to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900000 shares. Now switching to guidance. Given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17 for the full year 2023 we now expect C. F. Net product revenue of approximately 9.85 billion versus our prior range of 9.7 to 9.8 billion note that this revenue. Guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency, we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of. Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

Operating expense growth was driven as expected by continued investment in research and our pipeline throughout 2023 the most significant areas of increased investment versus prior year included the clinical studies for VX 548 in acute pain. The vans the captor triple in CF and for type one diabetes as well as build out of <unk>.

Abilities for our expanding pipeline in.

Charles Wagner: In addition, we continued our pre-commercial activities for exa-cel and other anticipated near term launches, third quarter 2023 non-GAAP operating income was $1.17 billion compared to $1.29 billion in the third quarter of 2022, third quarter 2023, non-GAAP earnings per share were $4.08, representing 2% growth compared to $4.01 in the third quarter of 2022. We ended the quarter with 13.6 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 year to date, we have completed nearly 10 transactions with total consideration of over $500 million. We've also. <unk> to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900000 shares. Now switching to guidance. Given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17 for the full year 2023 we now expect C. F. Net product revenue of approximately 9.85 billion versus our prior range of 9.7 to 9.8 billion note that this revenue. Guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency, we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of. Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

In addition, we continued our pre commercial activities for eggs or cell and other anticipated near term launches third quarter 2023 non-GAAP operating income was 1.17 billion compared to 1.29 billion in the third quarter of 2022.

Third quarter 2023, non-GAAP earnings per share were $4.08, representing 2% growth compared to $4.01 in the third quarter of 2022.

Charles Wagner: We ended the quarter with $13.6 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, year to date, we have completed nearly 10 transactions with total consideration of over $500 million. We've also. <unk> to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900000 shares. Now switching to guidance. Given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17 for the full year 2023 we now expect C. F. Net product revenue of approximately 9.85 billion versus our prior range of 9.7 to 9.8 billion note that this revenue. Guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency, we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of. Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

We ended the quarter with 13.6 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 year to date, we have completed nearly 10 transactions with total consideration of over $500 million. We've also.

Charles Wagner: We've also continued to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900,000 shares. Now switching to guidance. Given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17 for the full year 2023 we now expect C. F. Net product revenue of approximately 9.85 billion versus our prior range of 9.7 to 9.8 billion note that this revenue. Guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency, we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of. Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

Charles Wagner: We've also continued to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900,000 shares.

<unk> to allocate cash to share repurchases and year to date, we have spent approximately $285 million to repurchase approximately 900000 shares.

Charles Wagner: Now switching to guidance, given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17, for the full year 2023 we now expect CF Net product revenue of approximately $9.85 billion versus our prior range of $9.7 to $9.8 billion, note that this revenue guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency. we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of. Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

Now switching to guidance.

Given our strong year to date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on slide 17 for the full year 2023 we now expect C. F. Net product revenue of approximately 9.85 billion versus our prior range of 9.7 to 9.8 billion note that this revenue.

Guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency, we are maintaining our 2023 guidance for combined non-GAAP R&D acquired IP R&D and SG&A expenses in a range of 4.1 to 4.2 billion. We continue to invest the majority of.

Charles Wagner: We are maintaining our 2023 guidance for combined non-GAAP R&D acquired IPR&D and SG&A expenses in a range of $4.1 to $4.2 billion, we continue to invest the majority of our operating expenses into R&D given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

Our operating expenses into R&D, given the momentum in our multiple mid and late stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion dollar opportunities represented by our programs with near term launch potential while continuing to leverage and attractive business model afforded by.

Charles Wagner: We are also funding the expansion of our commercial capabilities in anticipation of the multibillion 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. Due to an increase in our current year U S. R&D tax credit estimate we are lowering guidance for our projected full year 2023, non-GAAP effective tax rate by 100 basis points to a range of 20% to 21% versus the prior range of 21% to 22% in. In closing vertex delivered excellent results yet again in Q3 twenty-three achieving strong revenue growth important regulatory milestones continued clinical trial progress and ongoing investments both internally and externally as we continued to advance our programs to closeout 2023 and head into 'twenty 'twenty four we anticipate further. Important milestones as highlighted on slide 18 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.

Our focus in specialty markets.

Charles Wagner: Due to an increase in our current year US R&D tax credit estimate we are lowering guidance for our projected full year 2023, non-GAAP effective tax rate by 100 basis points to a range of 20% to 21% versus the prior range of 21% to 22%. In closing vertex delivered excellent results yet again in Q3 twenty-three achieving strong revenue growth important regulatory milestones continued clinical trial progress and ongoing investments both internally and externally as we continued to advance our programs to closeout 2023 and head into 'twenty 'twenty four we anticipate further. Important milestones as highlighted on slide 18 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.

Due to an increase in our current year U S. R&D tax credit estimate we are lowering guidance for our projected full year 2023, non-GAAP effective tax rate by 100 basis points to a range of 20% to 21% versus the prior range of 21% to 22% in.

Charles Wagner: In closing Vertex delivered excellent results yet again in Q3 '23 achieving strong revenue growth, important regulatory milestones, continued clinical trial progress and ongoing investments both internally and externally, as we continued to advance our programs to closeout 2023 and head into 2024, we anticipate further important milestones as highlighted on slide 18 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 Q3 twenty-three achieving strong revenue growth important regulatory milestones continued clinical trial progress and ongoing investments both internally and externally as we continued to advance our programs to closeout 2023 and head into 'twenty 'twenty four we anticipate further.

Important milestones as highlighted on slide 18 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.

Operator: We will now begin the question and answer session, to ask a question you may press star then one on your Touchtone phone, if you're using a speakerphone, please pick up your handset before pressing the keys, to withdraw your question please press star then two and at this time, we'll pause momentarily to assemble our roster. And the first question will come from Geoff Meacham with Bank of America. Please go ahead.

To withdraw your question. Please press Star then two and at this time, we'll pause momentarily to assemble our roster.

Operator: And the first question will come from Geoff Meacham with Bank of America. Please go ahead.

And the first question will come from Geoff Meacham with Bank of America. Please go ahead.

Geoff Meacham: Good afternoon everyone thanks so much for the question (inaudible) Geoff sorry you're garbled, We can't understand you. Yeah. And when we did our ends up I will come back to you yeah, that's better thanks. Yes. So first question on a T seems like a much more difficult indication than initially thought you know what at a high level what would you characterize that as is it is it just the mechanism is at. The bar for you know risk benefit or is it the molecules itself. And the second the second question is when you look to advance a catheter and the data maybe help us with how rapidly you think you could roll reimbursement out across Europe in an O U S indications I know I wasn't sure. If this was part of your. You're a portfolio agreements are you if you had to renegotiate that thank you. Yeah sure thing this is Ralph I'll, let me break that into two questions I'll take the first part on a a T and I'll ask them.

Geoff Meacham: Good afternoon everyone thanks so much for the question (inaudible)

Good afternoon, everyone. Thanks, so much for the question.

Geoff Meacham: Geoff sorry you're garbled, We can't understand you, mind if we do the next then come back to you? Yeah that's better thanks And when we did our ends up I will come back to you yeah, that's better thanks. Yes. So first question on a T seems like a much more difficult indication than initially thought you know what at a high level what would you characterize that as is it is it just the mechanism is at. The bar for you know risk benefit or is it the molecules itself. And the second the second question is when you look to advance a catheter and the data maybe help us with how rapidly you think you could roll reimbursement out across Europe in an O U S indications I know I wasn't sure. If this was part of your. You're a portfolio agreements are you if you had to renegotiate that thank you. Yeah sure thing this is Ralph I'll, let me break that into two questions I'll take the first part on a a T and I'll ask them.

Susie Lisa: Geoff sorry you're garbled, We can't understand you, probably go to the next then come back to you? Yeah that's better thanks And

Okay.

So.

Okay.

Yes.

Okay.

And death.

Geoff Meacham: So first question on AAT, seems like a much more difficult indication than initially thought, you know what, at a high level what would you characterize that asset, is it just the mechanism is it the bar for risk/benefit or is it the molecules itself? and the second question is, when you look to Vanzacaftor in the data, maybe help us with how rapidly you think you could roll reimbursement out across Europe and in OUS indications, I wasn't sure if this was part of your portfolio agreements or if you had to renegotiate that, thank you. Yeah sure thing this is Ralph I'll, let me break that into two questions I'll take the first part on a a T and I'll ask them.

Oh, Yeah, sorry, yeah, you're garbled.

We can't understand you.

Yeah.

And when we did our ends up I will come back to you yeah, that's better thanks.

Yes.

So first question on a T seems like a much more difficult indication than initially thought you know what at a high level what would you characterize that as is it is it just the mechanism is at.

The bar for you know risk benefit or is it the molecules itself.

And the second the second question is when you look to advance a catheter and the data maybe help us with how rapidly you think you could roll reimbursement out across Europe in an O U S indications I know I wasn't sure. If this was part of your.

Geoff Meacham: Yeah sure thing this is Reshma, let me break that into two questions, I'll take the first part on a a T and I'll ask them. Stewart to comment on the vans, a catheter and our plans for launching a globally. You know, Jeff the the particular issue with the VX 864 molecule in a a T. D is a non serious rash. That's it that's what it is and when you see this it's almost always molecule specific so no. It's not the mechanism of action. This is. Is where the portfolio strategy is really important and comes into play VX 634, and VX 668, which are the next two molecules. They remain in that phase one development and we're looking forward to getting those results and the data that will be a 24 data that when we get to see those. Results and select a molecule or molecules and settle on next steps, let me turn it over to Stuart to talk about vans and to clarify. The study is a global study and the intent is for global regulatory submissions and for a global launch Stuart. Yeah, Jeff so on expectations for access and reimbursement outside of the U S. As restaurants said. Importantly, this study is a head to head comparison with Tri CAFTA to your specific question was vans. The CAFTA imagined when we embarked on some of our portfolio agreements. It was some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what vans. After will prove to be it isn't in all of our reimbursement agreements just to be clear, but if the product can deliver the kind of profile that we expect I would expect like we did with Tri caster that we will be the kind of industry benchmarks for forgetting to access patients across X U S markets.

Geoff Meacham: Yeah sure thing this is Reshma, let me break that into two questions, I'll take the first part on AAT and I'll ask Stewart to comment on the Vanzacaftor and our plans for launching globally.

You're a portfolio agreements are you if you had to renegotiate that thank you.

Yeah sure thing this is Ralph I'll, let me break that into two questions I'll take the first part on a a T and I'll ask them.

Stewart to comment on the vans, a catheter and our plans for launching a globally.

Geoff Meacham: You know, Jeff the particular issue with the VX-864 molecule in AATD is a non serious rash, that's it, that's what it is and when you see this it's almost always molecule specific so no it's not the mechanism of action, this is where the portfolio strategy is really important and comes into play VX-634, and VX-668, which are the next two molecules, they remain in that phase one development and we're looking forward to getting those results and the data event will be a 24 data event that when we get to see those results and select a molecule or molecules and settle on next steps, let me turn it over to Stuart to talk about vans and to clarify. The study is a global study and the intent is for global regulatory submissions and for a global launch Stuart. Yeah, Jeff so on expectations for access and reimbursement outside of the U S. As restaurants said. Importantly, this study is a head to head comparison with Tri CAFTA to your specific question was vans. The CAFTA imagined when we embarked on some of our portfolio agreements. It was some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what vans. After will prove to be it isn't in all of our reimbursement agreements just to be clear, but if the product can deliver the kind of profile that we expect I would expect like we did with Tri caster that we will be the kind of industry benchmarks for forgetting to access patients across X U S markets.

Geoff Meacham: You know Geoff, the particular issue with the VX-864 molecule in AATD is a non serious rash, that's it, that's what it is and when you see this it's almost always molecule specific so no it's not the mechanism of action, this is where the portfolio strategy is really important and comes into play.

You know, Jeff the the particular issue with the VX 864 molecule in a a T. D is a non serious rash. That's it that's what it is and when you see this it's almost always molecule specific so no. It's not the mechanism of action. This is.

Geoff Meacham: VX-634, and VX-668, which are the next two molecules, they remain in Phase I development and we're looking forward to getting those results and the data event will be a 24 data event that when we get to see those results and select a molecule or molecules and settle on next steps, let me turn it over to Stuart to talk about Vanza and to clarify, the study is a global study and the intent is for global regulatory submissions and for a global launch, Stuart.

Is where the portfolio strategy is really important and comes into play VX 634, and VX 668, which are the next two molecules. They remain in that phase one development and we're looking forward to getting those results and the data that will be a 24 data that when we get to see those.

Results and select a molecule or molecules and settle on next steps, let me turn it over to Stuart to talk about vans and to clarify. The study is a global study and the intent is for global regulatory submissions and for a global launch Stuart.

Stuart Arbuckle: Yeah, Geoff so on expectations for access and reimbursement outside of the US, as Reshma said, importantly, this study is a head to head comparison with Trikafta to your specific question, was Vanzacaftor imagined when we embarked on some of our portfolio agreements? it was, some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what Vanzacaftor will prove to be it isn't in all of our reimbursement agreements just to be clear, but if the product can deliver the kind of profile that we expect I would expect like we did with Tri caster that we will be the kind of industry benchmarks for forgetting to access patients across X U S markets.

Yeah, Jeff so on expectations for access and reimbursement outside of the U S.

As restaurants said.

Importantly, this study is a head to head comparison with Tri CAFTA to your specific question was vans. The CAFTA imagined when we embarked on some of our portfolio agreements. It was some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what vans.

Stuart Arbuckle: It was, some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what Vanzacaftor will prove to be, it isn't in all of our reimbursement agreements just to be clear, but if the product can deliver the kind of profile that we expect, I would expect like we did with Trikafta that we will be the kind of industry benchmarks for forgetting to access patients across ex US markets.

After will prove to be it isn't in all of our reimbursement agreements just to be clear, but if the product can deliver the kind of profile that we expect I would expect like we did with Tri caster that we will be the kind of industry benchmarks for forgetting to access patients across X U S markets.

Geoff Meacham: Okay. Thank you guys.

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

Robyn Karnauskas: Alright thanks guys, it sounds like 24/25 its going to be a breakout year for Vertex, transformative in many ways, two questions for me, one on pain, Reshma thanks for clarifying your lining at the same time but we get all these investor questions saying are you concerned about the LSR 2b trial, maybe help us understand the strategy for why doing that at the same time and if you, if there's any risk, my second question is on PNP, so you said you'll have a specialist sales force, how do you market it in the context that Lyrica exists, even though it's now scheduled drug, maybe set expectations for what you're looking for for that data, thanks

Two questions for me one on pain restaurant, thanks for clarifying on blinding at the same time.

But we get all these investor question thing are you concerned about the adaptive trial.

Maybe help us understand the strategy of why doing that thing time, and if you if there is any risk.

My second question is on TNT.

So you said, you'll have a specialty sales force.

How do you market it in the context that lyrica exists, even though it's now scheduled drug maybe set expectations for what you're looking for for that data.

Yeah.

Reshma Kewalramani: Robyn, two questions on VX-548, one on the acute pain side and one on the neuropathic pain side, let me tackle acute pain and I'll ask Stuart to comment on our commercialization approach on the neuropathic side.

Reshma Kewalramani: So to ground everyone, the acute pain program is in it's entirety three pivotal trials, one is the abdominoplasty RCT, the second is the Bunionectomy RCT and the third is a single arm safety and effectiveness trial and the reason we are are planning to unblind, analyze and share the results all at the same time is because our goal is to secure a broad, moderate to severe acute pain label and in order to do that we need the results from all of these trials, so that's the reason for sharing the results all at the same time. with regard to P. N. P. I'll just frame it up with what we are looking to do in and how you may want to think about the profile and then I'll turn it over to Stuart for. Commercialization. Nation. The phase two study that's the study we have completed and expect to share the results before the end of this year. It is a study that has a lyrica reference arm. So it's not a comparison, but it's there so that we can assess the magnitude of the treatment effect and our goal here really is to have a medicine that can compete effectively and bring a better benefit risk profile than lyric. For this patient population. And just so that it's not missed one of the comments I made in my prepared remarks is we're now expanding our progress into the peripheral neuropathic pain area. With a study that we will initiate before end of year in what's called L. F R or lumbosacral radiculopathy, another kind of neuropathic pain Stuart Yeah, just to expand on that Robin very briefly so P. N. P is kind of an umbrella term, which is used to describe a collection of conditions all of which have as that cause nerve and <unk>.

We are planning to unwind analyze and share the results all at the same time is because our goal is to secure a broad.

Moderate to severe acute pain label and in order to do that we need the results from all of these trials. So that's the reason for sharing the results all at the same time with regard to P. N. P. I'll just frame it up with what we are looking to do in and how you may want to think about the profile and then I'll turn it over to Stuart for.

Reshma Kewalramani: With regard to PNP I'll just frame it up with what we are looking to do and how you may want to think about the profile and then I'll turn it over to Stuart for commercialization. The Phase II study, that's the study we have completed and expect to share the results before the end of this year, it is a study that has a Lyrica reference arm, so it's not a comparison, but it's there so that we can assess the magnitude of the treatment effect and our goal here really is to have a medicine that can compete effectively and bring a better benefit risk profile than Lyrica for this patient population. And just so that it's not missed one of the comments I made in my prepared remarks is we're now expanding our progress into the peripheral neuropathic pain area. With a study that we will initiate before end of year in what's called L. F R or lumbosacral radiculopathy, another kind of neuropathic pain Stuart Yeah, just to expand on that Robin very briefly so P. N. P is kind of an umbrella term, which is used to describe a collection of conditions all of which have as that cause nerve and <unk>.

Commercialization.

Nation. The phase two study that's the study we have completed and expect to share the results before the end of this year.

It is a study that has a lyrica reference arm. So it's not a comparison, but it's there so that we can assess the magnitude of the treatment effect and our goal here really is to have a medicine that can compete effectively and bring a better benefit risk profile than lyric.

Reshma Kewalramani: And just so that it's not missed, one of the comments I made in my prepared remarks is we're now expanding our progress into the peripheral neuropathic pain area with a study that we will initiate before end of year in what's called LFR or Lumbosacral Radiculopathy, another kind of neuropathic pain, Stuart. Yeah, just to expand on that Robin very briefly so P. N. P is kind of an umbrella term, which is used to describe a collection of conditions all of which have as that cause nerve and <unk>.

For this patient population.

And just so that it's not missed one of the comments I made in my prepared remarks is we're now expanding our progress into the peripheral neuropathic pain area.

With a study that we will initiate before end of year in what's called L. F R or lumbosacral radiculopathy, another kind of neuropathic pain Stuart Yeah, just to expand on that Robin very briefly so P. N. P is kind of an umbrella term, which is used to describe a collection of conditions all of which have as that cause nerve and <unk>.

Stuart Arbuckle: Yeah, just to expand on that Robyn very briefly, so PNP is kind of an umbrella term, which is used to describe a collection of conditions, all of which have as a cause nerve impairment, which causes pain, DPN, which as you know is this study which is ongoing with 548, obviously there the standard of care has been the gabapentinoids or as Reshma said, what we're looking to do there because there are approved therapies there which are generic is demonstrate an improved benefit risk profile to be able to compete successfully in that market segment in phase II. Studies, obviously going be very revealing in that regard. LSR is very different in D. P and I should say accounts for about 20% of all patients in the U S with a with P. M. P. That's 20% of approximately 10 million people L. S. Our accounts are over 40% of patients with a P. N P. There there are no products, which are specifically approved. For L. S. L. So we see that as a very significant opportunity as well. They are obviously with no approved therapies, it's likely that the comparator is going to be can we demonstrate that. Active pain relief versus placebo. One path I can do you have to look better I know lyric headsets aside arm, but I know a lot of doctors want looking better for reimbursement do you have to look better or just safer. We obviously know the issues with safety with Lyrica. Yeah, Yeah, Yeah. The point you make about the safety tolerability issues with Lyrica. A real. What we're looking for in this phase two program is. Change from baseline at the various doses with Lyrica as a reference arm not a comparator, but our goal here to be clear is to have a product VX 548 that has a better benefit risk profile that lyrica.

Hammond, which causes pain.

D P N, which as you know is this study which is ongoing with 548, obviously there the standard of care has been the Gaba pension origin is Rashmi said, what we're looking to do there because there are approved therapies, there which are generic is demonstrate an improved benefit risk profile to be able to compete successfully in that market segment in phase II.

Studies, obviously going be very revealing in that regard <unk> is very different in D. P and I should say accounts for about 20% of all patients in the U S with a with P. M. P. That's 20% of approximately 10 million people L. S. Our accounts are over 40% of patients with a P.

Stuart Arbuckle: LSR is very different, DPN I should say accounts for about 20% of all patients in the US with PNP, that's 20% of approximately 10 million people, LSR accounts are over 40% of patients with a PNP there there are no products which are specifically approved for LSR, so we see that as a very significant opportunity as well, they are obviously with no approved therapies, it's likely that the comparator is going to be, can we demonstrate that active pain relief versus placebo one path I can do you have to look better I know lyric headsets aside arm, but I know a lot of doctors want looking better for reimbursement do you have to look better or just safer. We obviously know the issues with safety with Lyrica. Yeah, Yeah, Yeah. The point you make about the safety tolerability issues with Lyrica. A real. What we're looking for in this phase two program is. Change from baseline at the various doses with Lyrica as a reference arm not a comparator, but our goal here to be clear is to have a product VX 548 that has a better benefit risk profile that lyrica.

N P. There there are no products, which are specifically approved.

For L. S. L. So we see that as a very significant opportunity as well. They are obviously with no approved therapies, it's likely that the comparator is going to be can we demonstrate that.

Active pain relief versus placebo.

Stuart Arbuckle: one plus if I can, do you have to look better? I know Lyrica is just a side arm, but I know a lot of doctors want it looking better for reimbursement, do you have to look better or just safer, we obviously know the issues with safety with Lyrica. Yeah, Yeah, Yeah. The point you make about the safety tolerability issues with Lyrica. A real. What we're looking for in this phase two program is. Change from baseline at the various doses with Lyrica as a reference arm not a comparator, but our goal here to be clear is to have a product VX 548 that has a better benefit risk profile that lyrica.

Robyn Karnauskas: one plus if I can, do you have to look better? I know Lyrica is just a side arm, but I know a lot of doctors want it looking better for reimbursement, do you have to look better or just safer, we obviously know the issues with safety with Lyrica.

One path I can do you have to look better I know lyric headsets aside arm, but I know a lot of doctors want looking better for reimbursement do you have to look better or just safer. We obviously know the issues with safety with Lyrica.

Yeah, Yeah, Yeah. The point you make about the safety tolerability issues with Lyrica.

Reshma Kewalramani: The point you make about the safety tolerability issues with Lyrica are real, what we're looking for in this Phase II program is change from baseline at the various doses with Lyrica as a reference arm, not a comparator, but our goal here to be clear is to have a product VX-548 that has a better benefit risk profile that Lyrica.

A real.

What we're looking for in this phase two program is.

Change from baseline at the various doses with Lyrica as a reference arm not a comparator, but our goal here to be clear is to have a product VX 548 that has a better benefit risk profile that lyrica.

Robyn Karnauskas: Great. Thanks, Thanks, guys.

Operator: The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.

Salveen Richter: Good afternoon thanks for taking my question, one here on the pain side with the LSR trial, can you help us understand why start this trial now versus waiting for the DPN trial to read out and get a better understanding of the profile there and then a second question on the sales and device program here, that seems to be partial dose with target enrollment again and I'm just wondering why in the context of maybe the de-risking that you saw in the naked cell approach. Thank you.

On the pain side with the MSR trial can you help us understand why start this trial now versus waiting for the D. P. N trial to read out and get a better understanding of the profile. There and then a second question on the sales and device program here.

That seems to be.

Partial dose with target enrollment again and I'm just wondering why in the context of maybe the de risking that you saw in the naked cell approach. Thank you.

Reshma Kewalramani: Sure thing, let me start with the VX-264 question and I'll go back to pain.

Let me start with the.

The VX 264 question and I'll go back to pain.

Reshma Kewalramani: The reason that we are at a partial dose with staggered dosing in the part A, part of the 264 program is because the cells + device is a first in man program and we are doing that to go slowly and ensure that we have sufficient time between patients to be able to assess safety and it is the way that the protocol is designed in consultation with global regulators, so that's the reason, it's because cells + device is a first in man trial. Let me go back now to VX, 548, and LFR and why now. It's really a very good question. The reason we started with D. P. N is because D. P N or diabetic peripheral neuropathy has and has had an established regulatory pathway as well as a established. Commercial marketplace. So that's why we started with a D. P. N. We started with it actually when we did the 150 program and that's the first. P N P. A peripheral neuropathic pain indication, we pursued when we started with VX 548, as the VX five for each study has gotten started and frankly as we near that completion, we've turned our attention to <unk>. It was always our intention to pursue a broad peripheral neuropathic pain label for. VX five Boyd just like we're pursuing a broad label in the acute pain setting. We recently completed our regulatory discussions on the L. S. R pain type and gained confirmation that L. S. Far from a regulatory perspective is a P. N P pain type as Stuart said medically scientifically falls under that umbrella of a peripheral neuropathic pain. Type and we completed our discussions with the regulators and confirm that it is indeed from a regulatory standpoint also a P. M. P type that's why we're starting the L. S. Our phase II study now and I got to tell you I'm terribly excited about that.

With staggered dosing in the part a part of the 264 program is because the cells plus device is a first in man program and we are doing that too.

To go slowly and ensure that we have sufficient time between patients to be able to assess safety and it is the way that the protocol is designed in consultation with global regulators. So that's the reason, it's because south plus device is a first in man trial.

Reshma Kewalramani: Let me go back now to VX-548, and LSR and why now, it's really a very good question, the reason we started with DPN is because DPN or Diabetic Peripheral Neuropathy has and has had an established regulatory pathway as well as a established commercial marketplace, so that's why we started with DPN, we started with it actually when we did the 150 program and that's the first PNP or Peripheral Neuropathic pain indication we pursued when we started with VX-548, as the VX five for each study has gotten started and frankly as we near that completion, we've turned our attention to <unk>. It was always our intention to pursue a broad peripheral neuropathic pain label for. VX five Boyd just like we're pursuing a broad label in the acute pain setting. We recently completed our regulatory discussions on the L. S. R pain type and gained confirmation that L. S. Far from a regulatory perspective is a P. N P pain type as Stuart said medically scientifically falls under that umbrella of a peripheral neuropathic pain. Type and we completed our discussions with the regulators and confirm that it is indeed from a regulatory standpoint also a P. M. P type that's why we're starting the L. S. Our phase II study now and I got to tell you I'm terribly excited about that.

Let me go back now to VX, 548, and LFR and why now.

It's really a very good question. The reason we started with D. P. N is because D. P N or diabetic peripheral neuropathy has and has had an established regulatory pathway as well as a established.

Commercial marketplace. So that's why we started with a D. P. N. We started with it actually when we did the 150 program and that's the first.

Reshma Kewalramani: As the VX-548 study has gotten started and frankly as we near that completion, we've turned our attention to LSR, it was always our intention to pursue a broad Peripheral Neuropathic Pain label for VX-458, just like we're pursuing a broad label in the acute pain setting. We recently completed our regulatory discussions on the L. S. R pain type and gained confirmation that L. S. Far from a regulatory perspective is a P. N P pain type as Stuart said medically scientifically falls under that umbrella of a peripheral neuropathic pain. Type and we completed our discussions with the regulators and confirm that it is indeed from a regulatory standpoint also a P. M. P type that's why we're starting the L. S. Our phase II study now and I got to tell you I'm terribly excited about that.

P N P. A peripheral neuropathic pain indication, we pursued when we started with VX 548, as the VX five for each study has gotten started and frankly as we near that completion, we've turned our attention to <unk>. It was always our intention to pursue a broad peripheral neuropathic pain label for.

VX five Boyd just like we're pursuing a broad label in the acute pain setting.

Reshma Kewalramani: We recently completed our regulatory discussions on the LSR pain type and gained confirmation that LSR, from a regulatory perspective, is a PNP pain type, as Stuart said medically, scientifically falls under that umbrella of a peripheral neuropathic pain type and we completed our discussions with the regulators and confirm that it is indeed from a regulatory standpoint also a PNP type, that's why we're starting the LSR Phase II study now, and I got to tell you I'm terribly excited about that.

We recently completed our regulatory discussions on the L. S. R pain type and gained confirmation that L. S. Far from a regulatory perspective is a P. N P pain type as Stuart said medically scientifically falls under that umbrella of a peripheral neuropathic pain.

Type and we completed our discussions with the regulators and confirm that it is indeed from a regulatory standpoint also a P. M. P type that's why we're starting the L. S. Our phase II study now and I got to tell you I'm terribly excited about that.

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

Phil Nadeau: Hi, good afternoon thanks for taking our questions, a couple follow ups from us, first on pain, investors saw the new England Journal of Medicine editorial over the summer, there was somewhat skeptical of 548, and it's a topic of debate, could you respond to that editorial? what do you think the author got wrong or where do you disagree with the author, and then second a follow up on Vanza on the prepared remarks, you mentioned that Vanza was going to drive intermediate growth to the franchise can you elaborate on those comments a bit more, what new patient populations or opportunities could Vanza explore that Trikafta currently can't. Thanks.

So the new England Journal Medicine editorial over the summer.

There was somewhat skeptical of 548, and it's a topic of debate could you respond to that editorial would what do you think the author go wrong or where do you.

Disagree with the author.

And then second a follow up on the prepared remarks, you mentioned that the answer was going to drive intermediate growth of the franchise can you elaborate on those comments a bit more what new patient populations or opportunities.

Uh huh.

For that that truck after currently Kat. Thanks.

Reshma Kewalramani: Yeah sure thing, You know Phil when I think about the distillation of the editorial, I think it comes down to this is the Holy Grail of pain in terms of targets, there looks to be very promising results, it's a Phase II study, how should we think about the magnitude of the treatment effect, how should we think about it in terms of the effect and the potential not only versus placebo, but versus opioids, and then maybe a desire to learn a little bit more about the secondary endpoints. and what I would say is we're going to have a far bigger study 2000 people at all. There's a thousand people in the Abdominoplasty study another 1000 people in the Bunionectomy study and another 250 people in the safety and effectiveness study and we'll have all the data we need to make a full assessment in this phase III trial. So I think the best answer is let's look to <unk>. Words, the phase three trial and I agree the phase II results are very promising let me turn it over to Stuart to talk about vans. Bill on the on vans or I would really think about the opportunity for patients to be initiated on vanda to be threefold. One is people who are currently on an existing see FTR modulator, but if we deliver the sort of profile with vans or that we're hoping to versus try CAFTA. They may want to be switched onto Davanzo CAFTA then. You've got patients who have not yet been initiated on a C. F. T. All modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6000, just over 6000 patients globally, now who Betsy discontinued a C. F. D. A modulator. So they've wanted to be honest C. F D. A modulator, but for a variety of reasons I've had. Discontinue as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried. So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

So when I think about the distillation of the editorial I think it comes down to this is the Holy Grail of pain in terms of targets.

There looks to be a very promising results.

It's a phase two study how should we think about the magnitude of the treatment effect, how should we think about it in terms of.

The effect and the potential not only versus placebo, but versus opioids, and then maybe a desire to learn a little bit more about the secondary endpoints and what I would say is we're going to have a far bigger study 2000 people at all.

Reshma Kewalramani: And what I would say is we're going to have a far bigger study 2,000 people in all, there's a thousand people in the Abdominoplasty study, another 1000 people in the Bunionectomy study and another 250 people in the safety and effectiveness study and we'll have all the data we need to make a full assessment in this phase III trial. So I think the best answer is let's look to <unk>. Words, the phase three trial and I agree the phase II results are very promising let me turn it over to Stuart to talk about vans. Bill on the on vans or I would really think about the opportunity for patients to be initiated on vanda to be threefold. One is people who are currently on an existing see FTR modulator, but if we deliver the sort of profile with vans or that we're hoping to versus try CAFTA. They may want to be switched onto Davanzo CAFTA then. You've got patients who have not yet been initiated on a C. F. T. All modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6000, just over 6000 patients globally, now who Betsy discontinued a C. F. D. A modulator. So they've wanted to be honest C. F D. A modulator, but for a variety of reasons I've had. Discontinue as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried. So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

There's a thousand people in the Abdominoplasty study another 1000 people in the Bunionectomy study and another 250 people in the safety and effectiveness study and we'll have all the data we need to make a full assessment in this phase III trial. So I think the best answer is let's look to <unk>.

Reshma Kewalramani: So I think the best answer is let's look towards, the Phase III trial and I agree the Phase II results are very promising, let me turn it over to Stuart to talk about Vanza. Bill on the on vans or I would really think about the opportunity for patients to be initiated on vanda to be threefold. One is people who are currently on an existing see FTR modulator, but if we deliver the sort of profile with vans or that we're hoping to versus try CAFTA. They may want to be switched onto Davanzo CAFTA then. You've got patients who have not yet been initiated on a C. F. T. All modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6000, just over 6000 patients globally, now who Betsy discontinued a C. F. D. A modulator. So they've wanted to be honest C. F D. A modulator, but for a variety of reasons I've had. Discontinue as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried. So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

Reshma Kewalramani: So I think the best answer is let's look towards, the Phase III trial and I agree the Phase II results are very promising, let me turn it over to Stuart to talk about Vanza.

Reshma Kewalramani: Phil on the on Vanza I would really think about the opportunity for patients to be initiated on Vanza to be threefold, one is people who are currently on an existing CFTR modulator, but if we deliver the sort of profile with Vanza that we're hoping to versus Trikafta, they may want to be switched onto Vanzacaftor, then you've got patients who have not yet been initiated on a C. F. T. All modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6000, just over 6000 patients globally, now who Betsy discontinued a C. F. D. A modulator. So they've wanted to be honest C. F D. A modulator, but for a variety of reasons I've had. Discontinue as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried. So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

Words, the phase three trial and I agree the phase II results are very promising let me turn it over to Stuart to talk about vans.

Bill on the on vans or I would really think about the opportunity for patients to be initiated on vanda to be threefold. One is people who are currently on an existing see FTR modulator, but if we deliver the sort of profile with vans or that we're hoping to versus try CAFTA. They may want to be switched onto Davanzo CAFTA then.

Reshma Kewalramani: Then you've got patients who have not yet been initiated on a CFTR modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6,000, just over 6,000 patients globally now, who have actually discontinued a CFTR modulator, so they've wanted to be on a CFTR modulator, but for a variety of reasons they've had to discontinue. as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried. So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

You've got patients who have not yet been initiated on a C. F. T. All modulator, that's a relatively small number of patients, but really the big opportunity for growth is there's about 6000, just over 6000 patients globally, now who Betsy discontinued a C. F. D. A modulator. So they've wanted to be honest C. F D. A modulator, but for a variety of reasons I've had.

Reshma Kewalramani: As I said that's over 6,000 patients now around the world, we don't often talk about discontinuation from our CFTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients, we know they would like to be on a CFTR modulator, because they've previously tried and so we think they could be patients who are very interested in Vanza, if we deliver the kind of profile what we're expecting.

Discontinue as I say, that's over 6000 patients now around the world. We don't often talk about discontinuation from Aussie FTR modulators, because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a C. S. T. L modulator, because they've previously tried.

So we think they could be patients who are very interested in vans that if we deliver the kind of profile what we're expecting.

Phil Nadeau: That's very helpful. Thanks for taking our questions.

Okay.

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 and congrats on all the progress, one question again staying on DPN study, could you remind us how prevalent is the opioid use in this setting because from our reading it seems like, it is more a third line agent and is the thought to replace Lyrica in that setting? or is it more like hope likely to replace opioids in that setting?, how are you thinking about the profile of the drugs, thank you.

One question again.

Staying on DP and study.

So could you remind us how prevalent is the opioid use in this setting because from a reading it seems like.

It is more a third line agent.

And as the talk to replace Lyrica in that setting or is it more like oops elected to replace look good in that setting I mean, how are you thinking about the profile of the drugs.

Thank you.

Reshma Kewalramani: Sure thing, I'll ask Stuart to talk about the what is being used DPN today. Yeah Mohit. There is a lot of polypharmacy going on in D. P. N right now largely because the efficacy of the various classes of pain medicines, which are available today is pretty variable. So you do see patients who are on on a nonsteroidal <unk> you see a lot of people who are on the Gaba pension noise, which have been studied and approved. Then you also do see a pair it parents of parents patients. On opioids as well so it really is a disease characterized by sort of polypharmacy large lead you to either variable efficacy and all the adverse events of the currently available therapies. That's why we're so excited about the prospect of FIFO rate being able to establish a new standard of care for these patients.

Reshma Kewalramani: Sure thing, I'll ask Stuart to talk about the what is being used DPN today.

Stuart talk about.

The what is being used in D. P M. Today.

Stuart Arbuckle: Yeah Mohit, there is a lot of polypharmacy going on in DPN right now, largely because the efficacy of the various classes of pain medicines, which are available today is pretty variable, so you do see patients who are on a non-steroidals, you see a lot of people who are on the Gabapentinoids, which have been studied and approved there you also do see patients on opioids as well, so it really is a disease characterized by sort of polypharmacy large lead you to either variable efficacy and all the adverse events of the currently available therapies, that's why we're so excited about the prospect 458 being able to establish a new standard of care for these patients.

Yeah Mohit.

There is a lot of polypharmacy going on in D. P. N right now largely because the efficacy of the various classes of pain medicines, which are available today is pretty variable. So you do see patients who are on on a nonsteroidal <unk> you see a lot of people who are on the Gaba pension noise, which have been studied and approved.

Then you also do see a pair it parents of parents patients.

On opioids as well so it really is a disease characterized by sort of polypharmacy large lead you to either variable efficacy and all the adverse events of the currently available therapies. That's why we're so excited about the prospect of FIFO rate being able to establish a new standard of care for these patients.

Mohit Bansal: Excellent. Thank you.

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

Jessica Fye: Hey guys Good afternoon thanks for taking my question, the press release makes mention of Vertex's portfolio approach to R&D and additional NaV1.8 and 1.7 inhibitors you're working on, how far along in development is the next most advanced 1.8 inhibitor behind VX-548, and do you have any dual 1.8 and 1.7 inhibitors. Yeah, Hey, welcome back Jeff.

<unk> NAV, one plenty and 1.7 inhibitor as you're working on how far along in development is the next most advanced.

One eight inhibitor behind VX 548, and do you have any dual one eight and $1 seven inhibitors.

Yeah, Hey, welcome back Jeff.

Reshma Kewalramani: Yeah, Hey, welcome back Jess, Really terrific question, The portfolio strategy as you've seen it play out in CF is authentically and reproducibly extended across our R&D pipeline, so as it pertains to pain, then next NaV1.8 inhibitors are already in the clinic in Phase I trials and we have more after that making their way through the research part of our organization. In terms of NaV1.7, they are in the research stage and making very good progress and we see the NaV1.7 as potentially for use as a single agent and we also see the real opportunity for combining NaV1.7 and 1.8 and just for all of the others who are following along, the reason I say that and the reason why I think it's an excellent question is that the way that the action potential works in the periphery in transducing the pain signal is that there is a stimulation of the action potential and then the propagation and NaV 1.7 works on that stimulation of the action potential and NaV1.8 works on that propagation, so we see a lot of opportunity in the combination, but we also see opportunity of our NaV1.7 in and of itself.

Really terrific question.

The portfolio strategy as you've seen it play out in CF is.

Centrically and reproducible.

Extended across our R&D pipeline.

As it pertains to pain, then next NAV 1.8 inhibitors are already in the clinic in phase one trials.

And we have more after that making their way through the.

Reshma Kewalramani: In terms of NaV1.7, they are in the research stage and making very good progress and we see the NaV1.7 as potentially for use as a single agent and we also see the real opportunity for combining NaV1.7 and 1.8 and just for all of the others who are following along, the reason I say that and the reason why I think it's an excellent question is that the way that the action potential works in the periphery in transducing the pain signal is that there is a stimulation of the action potential and then the propagation and NaV 1.7 works on that stimulation of the action potential and NaV1.8 works on that propagation, so we see a lot of opportunity in the combination, but we also see opportunity of our NaV1.7 in and of itself.

The research part of our organization.

In terms of NAV 1.7, they are in the research stage and making very good progress and we see the NAV one seven as potentially.

Or use.

As a single agent and we also see the real opportunity for combining NAV, one seven and one eight and just for all of the others who are following along the reason I say that and the reason why I think it's an excellent question is that the the way that.

Reshma Kewalramani: is that the way that the action potential works in the periphery in transducing the pain signal is that there is a stimulation of the action potential and then the propagation and NaV 1.7 works on that stimulation of the action potential and NaV1.8 works on that propagation, so we see a lot of opportunity in the combination, but we also see opportunity of our NaV1.7 in and of itself.

The action potential works in the periphery in trends do you think the pain signal is that there is a.

A stimulation of the action potential and then the propagation and NAV 1.7 works on that stimulation of the action potential and NAV. One eight works on that propagation. So we see a lot of opportunity in the combination, but we also see opportunity of our NAV, one seven in and of itself.

Jessica Fye: Thank you.

Operator: The next question will come from David Risinger with Leerink partners. Please go ahead.

David Reed Risinger: Yes, thanks very much, I have two questions please, first, if VX-548 succeeds in Phase II and DPN in coming months, how do you plan to conduct Phase III? do you plan to go it alone? and could you complete Phase III in '25, or likely not until '26? and then regarding VX-548 acute pain Phase III studies, how should we expect rescue medicine used essentially benefit patients in the placebo arms and how will rescue medicine use be disclosed? thanks very much.

I have two questions. Please first.

<unk> five <unk> succeed in phase two and DPM coming months, how do you plan to conduct phase III do you plan to go it alone and could you complete phase three in 'twenty, five or likely not until 'twenty six and then regarding VX 548 acute pain phase three studies.

How should we expect rescue medicine used essentially benefit patients in the placebo arms and how will rescue medicine use be disclosed thanks very much.

Reshma Kewalramani: Hey David, Let me start the answer to both of these questions, but the PNP question has a component of could we go at it alone? and so I want to make sure that. Stuart touches on it let me cut to the punch line. For acute pain and for neuropathic pain, both in terms of diabetic neuropathy and in terms of L. S. SAR. This lumbosacral radiculopathy, we're going to do that development by ourselves and we are going to commercialize by ourselves both of these acute.

Reshma Kewalramani: Hey David, Let me start the answer to both of these questions, but the PNP question has a component of could we go at it alone? and so I want to make sure that Stuart touches on it, let me cut to the punch line.

Has a component of can we go at it alone and so I want to make sure that.

Stuart touches on it let me cut to the punch line.

For acute pain and for neuropathic pain, both in terms of diabetic neuropathy and in terms of L. S. SAR. This lumbosacral radiculopathy, we're going to do that development by ourselves and we are going to commercialize by ourselves both of these acute.

Reshma Kewalramani: For acute pain and for neuropathic pain, both in terms of diabetic neuropathy and in terms of LSR, this Lumbosacral Radiculopathy, we're going to do the development by ourselves and we are going to commercialize by ourselves, both of these acute pain and neuropathic pain are absolutely vertexian diseases, if I can call it that, in terms of commercialization, I'll ask Stuart to comment a little bit more on commercializing, our neuropathic pain and I'll come back to tell you about acute pain, a rescue meds et cetera.

Pain and neuropathic pain.

Absolutely vertex seeing diseases, if I can call it that in terms of commercialization.

I'll ask Stuart to comment a little bit more on commercializing, our neuropathic pain and I'll come back to tell you about acute pain, a rescue meds et cetera.

Stuart Arbuckle: David So kind of building on what I said about this being a disease state, which unfortunately for patients is characterized by polypharmacy and so patients are often seeking superior pain relief to what they are getting, it is heavily influenced and or treated by specialists for DPN and indeed for LSR as well and so for both of those pain states within PNP overall, we believe we can achieve success commercially with a specialty sales force, as a result of wanting to go alone commercially, we're going to be doing the studies in DPN and hopefully in LSR Phase III studies are successful in Phase II ourselves as well. And David to round it out with your questions on acute pain. The we have thought through very carefully as we did in the phase II portion of the study the same in the phase III portion of the acute pain studies. About the use of rescue medicines and how to consider the statistical analysis plan in that light and there are. It's it's been very well considered am in there so. I don't have much more to say other than the use of rescue. Rescue medicines of course will be disclosed in the in the publications and when we share the results, but how to think about it has been a deeply considered and well accounted for just as it was in phase two I think there was a question in there. About phase three and the peripheral neuropathic pain structure I'll focus my comments on VPN. That one will be a it will be designed with the FDA, we haven't yet had our end of phase two meeting. And therefore, I can't give you specifics on what that program will look like. But that's exactly what will be the next step once we have the phase II D. P. N results assuming they are positive.

By specialists for D. P N and indeed for <unk> as well and so for both of those pain states within a P. N. P. Overall, we believe we can achieve success commercially with a specialty sales force as a result of wanting to go alone commercially we're going to be doing the studies in VPN and hopefully an L. S.

Our phase III studies are successful in phase two ourselves as well.

And David to round it out with your questions on acute pain.

Stuart Arbuckle: And David to round it out with your questions on acute pain, we have thought through very carefully, as we did in the Phase II portion of the study, the same in the Phase III portion of the acute pain studies about the use of rescue medicines and how to consider the statistical analysis plan in that light and there are, it's been very well considered in there so, I don't have much more to say other than the use of rescue. Rescue medicines of course will be disclosed in the in the publications and when we share the results, but how to think about it has been a deeply considered and well accounted for just as it was in phase two I think there was a question in there. About phase three and the peripheral neuropathic pain structure I'll focus my comments on VPN. That one will be a it will be designed with the FDA, we haven't yet had our end of phase two meeting. And therefore, I can't give you specifics on what that program will look like. But that's exactly what will be the next step once we have the phase II D. P. N results assuming they are positive.

The we have thought through very carefully as we did in the phase II portion of the study the same in the phase III portion of the acute pain studies.

About the use of rescue medicines and how to consider the statistical analysis plan in that light and there are.

It's it's been very well considered am in there so.

Stuart Arbuckle: I don't have much more to say other than the use of rescue medicines of course will be disclosed in the in the publications and when we share the results, but how to think about it has been a deeply considered and well accounted for just as it was in phase two. I think there was a question in there. About phase three and the peripheral neuropathic pain structure I'll focus my comments on VPN. That one will be a it will be designed with the FDA, we haven't yet had our end of phase two meeting. And therefore, I can't give you specifics on what that program will look like. But that's exactly what will be the next step once we have the phase II D. P. N results assuming they are positive.

I don't have much more to say other than the use of rescue.

Rescue medicines of course will be disclosed in the in the publications and when we share the results, but how to think about it has been a deeply considered and well accounted for just as it was in phase two I think there was a question in there.

Stuart Arbuckle: I think there was a question in there about Phase III and the peripheral neuropathic pain structure, I'll focus my comments on DPN, that one will be, will be designed with the FDA, we haven't yet had our end of Phase II meetings and therefore, I can't give you specifics on what that program will look like, but that's exactly what will be the next step, once we have the Phase II DPN results assuming they are positive.

About phase three and the peripheral neuropathic pain structure I'll focus my comments on VPN.

That one will be a it will be designed with the FDA, we haven't yet had our end of phase two meeting.

And therefore, I can't give you specifics on what that program will look like.

But that's exactly what will be the next step once we have the phase II D. P. N results assuming they are positive.

Thank you.

You bet. The next question will come from Evan Cybermen with BMO capital markets. Please go ahead.

You bet.

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

Evan Seigerman: Hi all, thank you so much for taking my question and congrats on the progress as always, So I wanted to talk about the implications of the recently released UK NICE appraisal of Trikafta, essentially indicating that was not cost effective for the UK system, I was under the impression that this was settled in 2019, could you maybe expand on the impact to UK franchise and steps to resolve, to ensure access in the UK. Thank you.

Under the impression that settled in 2019 could you maybe expand on the impact U K franchise and steps to resolve to ensure access in the U K. Thank you.

Stuart Arbuckle: Yeah Evan, so the first thing I'll say about the ongoing nice review is that this was an expected part of the contract that we negotiated with the NHS in 2019 so this isn't a surprise, that NICE is reviewing our medicines after four years on the market, so that's the first thing to say. As a part of the original contract we agreed with the NHS E and with with nice that we would collect and submit data or after a payer to being on the on the market. And we have done just that we submitted clinical trial data open label extension data and real world data from. The U K and I think. Yes. It's unusual I think to see a medicine, which is what I think we've seen with tricast as it performs perhaps even better in the real world than you expected having seen the phase III results because the results we've seen in the real world as you well know are absolutely extraordinary including things like reductions in exacerbations. Increases in life expectancy reductions in hospitalizations, a virtual elimination of lung transplants. So were pretty disappointed it's fair to say with the draft guidance from nice it is just that though its draft guidance. There was a period of consultation theres going to be a second. Nice Committee meeting and I, certainly feel confident that the full value of our medicines. Be reflected at the end of this process.

Stuart Arbuckle: Yeah Evan, so the first thing I'll say about the ongoing NICE review is that this was an expected part of the contract that we negotiated with the NHS in 2019, so this isn't a surprise that NICE is reviewing our medicines after four years on the market, so that's the first thing to say.

As a part of the original contract we agreed with the NHS E and with with nice that we would collect and submit data or after a payer to being on the on the market.

Stuart Arbuckle: As a part of the original contract we agreed with the NHS and with NICE that we would collect and submit data after a period of being on the market and we have done just that, we submitted clinical trial data, open label extension data and real world data from the UK and I think it's unusual I think to see a medicine, which is what I think we've seen with Trikafta that performs perhaps even better in the real world than you expected having seen the phase III results because the results we've seen in the real world as you well know are absolutely extraordinary including things like reductions in exacerbations. Increases in life expectancy reductions in hospitalizations, a virtual elimination of lung transplants. So were pretty disappointed it's fair to say with the draft guidance from nice it is just that though its draft guidance. There was a period of consultation theres going to be a second. Nice Committee meeting and I, certainly feel confident that the full value of our medicines. Be reflected at the end of this process.

And we have done just that we submitted clinical trial data open label extension data and real world data from.

Stuart Arbuckle: and I think it's unusual I think to see a medicine, which is what I think we've seen with Trikafta, that performs perhaps even better in the real world than you expected, having seen in the Phase III results, because the results we've seen in the real world as you well know are absolutely extraordinary, including things like reductions in exacerbations, increases in life expectancy, reductions in hospitalizations, a virtual elimination of lung transplants. So were pretty disappointed it's fair to say with the draft guidance from nice it is just that though its draft guidance. There was a period of consultation theres going to be a second. Nice Committee meeting and I, certainly feel confident that the full value of our medicines. Be reflected at the end of this process.

The U K and I think.

Yes.

It's unusual I think to see a medicine, which is what I think we've seen with tricast as it performs perhaps even better in the real world than you expected having seen the phase III results because the results we've seen in the real world as you well know are absolutely extraordinary including things like reductions in exacerbations.

Increases in life expectancy reductions in hospitalizations, a virtual elimination of lung transplants.

Stuart Arbuckle: So we're pretty disappointed, it's fair to say, with the draft guidance from NICE, it is just that though, its draft guidance, there was a period of consultation, there's going to be a second NICE Committee meeting and I certainly feel confident that the full value of our medicines will be reflected at the end of this process.

So were pretty disappointed it's fair to say with the draft guidance from nice it is just that though its draft guidance.

There was a period of consultation theres going to be a second.

Nice Committee meeting and I, certainly feel confident that the full value of our medicines.

Be reflected at the end of this process.

Evan Seigerman: Great. Thank you.

Operator: The next question will come from Liisa Bayco with Evercore ISI. Please go ahead.

Liisa Bayko: Hi there thanks for taking my question, I wanted to circle back to pain and just two questions for me, first of all, the article to the editorial New England Journal of Medicine did focused on overwhelmingly more females in the, two acute pain indications that you're using as examples, so maybe you can just speak to that and addressing sort of the underrepresentation of males, and then finally just if you could comment on any capabilities that you've been working on developing this is obviously a much different market to commercialize into than CF with you know a lot of generic competition and the need to get on hospital formulary etcetera, how are you building those capabilities that you're waiting for data.

Just two questions for me first of all the article said the editorial in the New England Journal.

Medicine did focus then on overwhelmingly more females and the.

Two acute pain indications that you're using as examples.

So maybe you can just speak to that and addressing sort of the underrepresentation of mail and then.

Finally, just if you could comment on any capabilities that you've been working on developing this is obviously a much different market to commercialize them too then.

Then.

The App with you know a lot of generic competition and the need to get on hospital formulary et cetera, how are you building.

The capabilities that you're waiting for data.

Reshma Kewalramani: Sure thing, Liisa this is Reshma, let me start and then I'll pass it over to Stuart, you know most companies, including our own, want to ensure that we have more people of color in our trials, more women in our trials and I guess we have succeeded, so I see the fact that 548 has many women as a positive. Perhaps one point to make underneath just underlying that comment is remember in the acute pain study one wasn't abdominoplasty study and Abdominoplasty is a procedure involving them. Fact in the belly kind of surgery it's. Some people call it a tummy tuck and that is a surgical procedure that more women undergo with regard to the commercialization of pain I'll turn it over to Stuart, but I want to frame up. The following concept. In the paint in the acute pain setting one of the most important elements that VX 548 could address is effective pain relief without the addiction potential of opioids and that part of it. This addiction potential of opioids is something that is not only of inter. Two vertex, but it's of interest to the community to policy makers to physicians and we see a lot of tailwind. And so as I turn it over to Stuart I'll I'll ask him to comment on our commercialization efforts, but also the tailwind we see Stewart.

You know most companies, including our own.

Want to ensure that we have more.

More people of color in our trials more women in our trials.

And I guess.

We have succeeded him so I see the the.

The fact that 548 has many women as a as a positive.

Reshma Kewalramani: Perhaps one point to make underneath, just underlying that comment is, remember in the acute pain study one was an abdominoplasty study and Abdominoplasty is a procedure involving fat in the belly kind of surgery, some people call it a tummy tuck and that is a surgical procedure that more women undergo. with regard to the commercialization of pain I'll turn it over to Stuart, but I want to frame up. The following concept. In the paint in the acute pain setting one of the most important elements that VX 548 could address is effective pain relief without the addiction potential of opioids and that part of it. This addiction potential of opioids is something that is not only of inter. Two vertex, but it's of interest to the community to policy makers to physicians and we see a lot of tailwind. And so as I turn it over to Stuart I'll I'll ask him to comment on our commercialization efforts, but also the tailwind we see Stewart.

Perhaps one point to make underneath just underlying that comment is remember in the acute pain study one wasn't abdominoplasty study and Abdominoplasty is a procedure involving them.

Fact in the belly kind of surgery it's.

Reshma Kewalramani: With regard to the commercialization of pain I'll turn it over to Stuart, but I want to frame up the following concept, in the acute pain setting, one of the most important elements that VX-548 could address is effective pain relief without the addiction potential of opioids and that part of it, this addiction potential of opioids, is something that is not only of interest to Vertex, but it's of interest to the community, to policy makers, to physicians and we see a lot of tailwind and so as I turn it over to Stuart I'll I'll ask him to comment on our commercialization efforts, but also the tailwinds we see, Stuart.

Some people call it a tummy tuck and that is a surgical procedure that more women undergo with regard to the commercialization of pain I'll turn it over to Stuart, but I want to frame up.

The following concept.

In the paint in the acute pain setting one of the most important elements that VX 548 could address is effective pain relief without the addiction potential of opioids and that part of it. This addiction potential of opioids is something that is not only of inter.

Two vertex, but it's of interest to the community to policy makers to physicians and we see a lot of tailwind.

And so as I turn it over to Stuart I'll I'll ask him to comment on our commercialization efforts, but also the tailwind we see Stewart.

Stuart Arbuckle: Yes so, your question about capabilities, I think we're trying to get the best of both worlds, we are trying to leverage the capabilities that have made us be successful to date and much of that is based around our ability to get reimbursement and access for our medicines. And also work with policymakers, with guidelines institutions etcetera, to support the appropriate use of effective medicines like ours. In this restaurant said, we're already seeing tailwinds if we can call them that in the. Pain market with people looking to kind of move away from the sort of restrictions that they've previously put in place for things like opioids in terms of who can prescribe them, for how long, for which patients, in which settings, to people looking at policy changes like the no pain Act, which we highlighted a couple of quarters ago now where people are looking to make sure that there are no financial barriers or disincentives to people doing the right thing and using a non opioid effective pain medicine, just because there are generic medicines available. So that's something that we're going to be looking to build on some of the capabilities that we've used to help us be successful, having said that we are going to be selling into a different segment of the <unk>. Market. This is obviously going to be a very a hospital institution driven. Sale and so we are looking to bring in and have brought in new capabilities. As we bought brought on our pain business unit people who are experienced. In that kind of institutional settings. So I would say, we're trying to get the best of both worlds leverage what we've been good at in the past, while bringing in people, who bring new knowledge skills and experience to the company as well.

Stuart Arbuckle: Yes so, to your question about capabilities, I think we're trying to get the best of both worlds, we are trying to leverage the capabilities that have made us be successful to date and much of that is based around our ability to get reimbursement and access for our medicines and also work with policymakers, with guidelines institutions etcetera, to support the appropriate use of effective medicines like ours.

Your question about capabilities I think we're trying to get the best of both worlds. We are trying to leverage the capabilities that have made us be successful to date and much of that is based around our ability to get reimbursement and access for our medicines.

And also work with policymakers.

With guidelines institutions etcetera to support the appropriate use of effective medicines like ours. In this restaurant said, we're already seeing tailwind if we can call them that in the.

Stuart Arbuckle: And as Reshma said, we're already seeing tailwinds, if we can call them that, in the pain market with people looking to kind of move away from the sort of restrictions that they've previously put in place for things like opioids, in terms of who can prescribe them, for how long, for which patients, in which settings. to people looking at policy changes like the NOPAIN act which we highlighted a couple of quarters ago now where people are looking to make sure that there are no financial barriers or disincentives to people doing the right thing and using a non opioid effective pain medicine, just because there are generic medicines available. So that's something that we're going to be looking to build on some of the capabilities that we've used to help us be successful, having said that we are going to be selling into a different segment of the <unk>. Market. This is obviously going to be a very a hospital institution driven. Sale and so we are looking to bring in and have brought in new capabilities. As we bought brought on our pain business unit people who are experienced. In that kind of institutional settings. So I would say, we're trying to get the best of both worlds leverage what we've been good at in the past, while bringing in people, who bring new knowledge skills and experience to the company as well.

Pain market with people looking to kind of move away from the sort of restrictions that they've previously put in place for things like opioids in terms of who can prescribe them for how long for which patients in which settings to people looking at policy changes like the no pain Act, which we highlighted a couple of quarters ago, now where people are looking to make sure that there.

Stuart Arbuckle: To people looking at policy changes like the NOPAIN act, which we highlighted a couple of quarters ago now, where people are looking to make sure that there are no financial barriers or disincentives to people doing the right thing and using a non-opioid effective pain medicine, just because there are generic medicines available. So that's something that we're going to be looking to build on some of the capabilities that we've used to help us be successful, having said that we are going to be selling into a different segment of the <unk>. Market. This is obviously going to be a very a hospital institution driven. Sale and so we are looking to bring in and have brought in new capabilities. As we bought brought on our pain business unit people who are experienced. In that kind of institutional settings. So I would say, we're trying to get the best of both worlds leverage what we've been good at in the past, while bringing in people, who bring new knowledge skills and experience to the company as well.

There are no financial barriers or disincentives to people doing the right thing and using a non opioid effective pain medicine, just because there are generic medicines available. So that's something that we're going to be looking to build on some of the capabilities that we've used to help us be successful, having said that we are going to be selling into a different segment of the <unk>.

Stuart Arbuckle: So that's something that we're going to be looking to build on, some of the capabilities that we've used to help us be successful, having said that we are going to be selling into a different segment of the market, this is obviously going to be a very a hospital-institution-driven sale and so we are looking to bring in and have brought in new capabilities as we brought on our pain business unit, people are experienced in that kind of institutional settings, so I would say, we're trying to get the best of both worlds, leverage what we've been good at in the past, while bringing in people who bring new knowledge skills and experience to the company as well.

Market. This is obviously going to be a very a hospital institution driven.

Stuart Arbuckle: And so we are looking to bring in and have brought in new capabilities as we brought on our pain business unit, people are experienced in that kind of institutional settings, so I would say, we're trying to get the best of both worlds, leverage what we've been good at in the past, while bringing in people who bring new knowledge skills and experience to the company as well.

Sale and so we are looking to bring in and have brought in new capabilities. As we bought brought on our pain business unit people who are experienced.

In that kind of institutional settings. So I would say, we're trying to get the best of both worlds leverage what we've been good at in the past, while bringing in people, who bring new knowledge skills and experience to the company as well.

Liisa Bayko: Thanks.

Operator: The next question will come from Michael Yee with Jefferies. Please go ahead.

Michael Yee: Hey guys thank you for the question and congrats on a great quarter, We had a follow up question on pain, and then a question on Vanza, on the acute and chronic pain, can you just remind me, since you've never disclose doses, should we expect that at the same doses used in the Phase II and also the Lyrica and Vicodin doses as control are basically the doses from the label and is that pretty well understood? and then from a safety tolerability standpoint, I think there was a QT study that completed, so was there anything to disclose there? that would be great to hear if that was the case, that would be a positive and then on vans I know that there was a question around non inferiority and superiority. And I know, it's powered potentially for superiority, but can you just remind us is there a magnitude of clinical meaningfulness on F&B et cetera. Deem to be meaningful or is it more the totality of everything as well like sweat chloride and the benefits that that may provide thank you so much.

We had a follow up question on pain, and then a question on vans.

<unk>.

The acute and chronic pain can you just remind me.

Since you've never disclose doses should we expect that at the <unk>.

<unk> doses used in the phase two and also the American Vicodin doses control are basically the doses from the label and is that pretty well understood.

And then from a.

Safety Tolerability standpoint, I think there was a qt study that completed so was there anything to disclose there that would be great to hear if that was the case that would be a positive and then on vans I know that there was a question around non inferiority and superiority.

Michael Yee: And then on Vanza I know that there was questions around non inferiority and superiority and I know it's powered potentially for superiority, but can you just remind us, is there a magnitude of clinical meaningfulness on FEV etcetera that you would deem to be meaningful, or is it more the totality of everything as well, like sweat chloride and the benefits that that may provide. thank you so much.

And I know, it's powered potentially for superiority, but can you just remind us is there a magnitude of clinical meaningfulness on F&B et cetera.

Deem to be meaningful or is it more the totality of everything as well like sweat chloride and the benefits that that may provide thank you so much.

Reshma Kewalramani: Sure thing Hey Mike, let me start and then I will ask Stuart (inaudible) towards the market research that Stuart and the team have done on Vanza and what is valued visa vis sweat chloride etcetera, but I'll go back to 548 to start and then I'll set up the clinical trial structure for Vanza. So to confirm on the VX 548, acute pain phase III trials

Towards the market research that Stuart and the team have done on vans.

And what is valued visa V sweat chloride et cetera, but I'll go back to 548 to start and then I'll set up the clinical trial structure for Vanda.

So to confirm on the VX 548, acute pain phase III trials.

Reshma Kewalramani: So to confirm on the VX-548 acute pain Phase III trials, it is exceptionally similar to the VX-548 Phase II trials, same pain conditions, Abdominoplasty and Bunionectomy, we selected the high dose, the dose that showed the benefit in the Phase II trial for the Phase III trial, and you are correct, our standard labeled doses for the opioids. Right. And on the. Phase two diabetic peripheral neuropathy trial correct. The Lyrica is standard doses from the label. The doses in the. Peripheral neuropathy phase two study are different than the acute pain doses, obviously, because one is chronic dosing and one is acute and we need to make the appropriate adjustments. So that we have the exposure we seek. But with regard to the reference arm correct. It is the standard dosing from the label. Lastly on vans a character. This is remember this is a study that is head to head versus tried CAFTA. The primary endpoint is P. P. F E V. One because that's the regulatory enabling endpoint. And recall, we have a key secondary endpoint that is on sweat chloride and this is very important because sweat chloride is the direct it's the most direct read out of C. F T our function. You know that there have been great debate about whether or not there is a ceiling on P. P. F E V. One we can't. We can't. Half better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better see FTR. Function benefit that would show up in terms of sweat chloride that is a secondary endpoint in the phase III trial, and that's what we've already studied and reported out in a variety of phase two trials and it does indeed. Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than try CAFTA over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

It is.

Exceptionally similar to the VX 548 phase two trials.

Same pain conditions, Abdominoplasty and Bunionectomy, we selected the high dose the dose that showed the benefit in the phase II trial for the phase three trial and you are correct our standard labeled doses for the op.

Reshma Kewalramani: And on the Phase II diabetic peripheral neuropathy trial, correct, the Lyrica is standard doses from the label, the doses in the Peripheral neuropathy phase two study are different than the acute pain doses, obviously, because one is chronic dosing and one is acute and we need to make the appropriate adjustments. So that we have the exposure we seek. But with regard to the reference arm correct. It is the standard dosing from the label. Lastly on vans a character. This is remember this is a study that is head to head versus tried CAFTA. The primary endpoint is P. P. F E V. One because that's the regulatory enabling endpoint. And recall, we have a key secondary endpoint that is on sweat chloride and this is very important because sweat chloride is the direct it's the most direct read out of C. F T our function. You know that there have been great debate about whether or not there is a ceiling on P. P. F E V. One we can't. We can't. Half better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better see FTR. Function benefit that would show up in terms of sweat chloride that is a secondary endpoint in the phase III trial, and that's what we've already studied and reported out in a variety of phase two trials and it does indeed. Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than try CAFTA over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

Reshma Kewalramani: And on the Phase II diabetic peripheral neuropathy trial, correct, the Lyrica is standard doses from the label,

Right.

Reshma Kewalramani: The doses in the Peripheral neuropathy Phase II study are different than the acute pain doses, obviously, because one is chronic dosing and one is acute and we need to make the appropriate adjustments so that we have the exposure we seek, but with regard to the reference arm, correct, it is the standard dosing from the label. Lastly on vans a character. This is remember this is a study that is head to head versus tried CAFTA. The primary endpoint is P. P. F E V. One because that's the regulatory enabling endpoint. And recall, we have a key secondary endpoint that is on sweat chloride and this is very important because sweat chloride is the direct it's the most direct read out of C. F T our function. You know that there have been great debate about whether or not there is a ceiling on P. P. F E V. One we can't. We can't. Half better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better see FTR. Function benefit that would show up in terms of sweat chloride that is a secondary endpoint in the phase III trial, and that's what we've already studied and reported out in a variety of phase two trials and it does indeed. Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than try CAFTA over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

And on the.

Phase two diabetic peripheral neuropathy trial correct. The Lyrica is standard doses from the label.

The doses in the.

Peripheral neuropathy phase two study are different than the acute pain doses, obviously, because one is chronic dosing and one is acute and we need to make the appropriate adjustments.

Reshma Kewalramani: Lastly on Vanzacaftor this is, remember ,this is a study that is head to head versus Trikafta, the primary endpoint is PPFEV1, because that's the regulatory enabling endpoint and recall, we have a key secondary endpoint that is on sweat chloride, and this is very important because sweat chloride is the direct, it's the most direct read out of CFTR our function. You know that there have been great debate about whether or not there is a ceiling on P. P. F E V. One we can't. We can't. Half better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better see FTR. Function benefit that would show up in terms of sweat chloride that is a secondary endpoint in the phase III trial, and that's what we've already studied and reported out in a variety of phase two trials and it does indeed. Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than try CAFTA over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

So that we have the exposure we seek.

But with regard to the reference arm correct. It is the standard dosing from the label.

Lastly on vans a character. This is remember this is a study that is head to head versus tried CAFTA.

The primary endpoint is P. P. F E V. One because that's the regulatory enabling endpoint.

Reshma Kewalramani: You know that there have been great debate about whether or not there is a ceiling on PPFEV1, we can't have better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better CFTR function benefit that would show up in terms of sweat chloride, that is a secondary endpoint in the Phase III trial, and that's what we've already studied and reported out in a variety of Phase II trials and it does indeed. Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than Trikafta over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

And recall, we have a key secondary endpoint that is on sweat chloride and this is very important because sweat chloride is the direct it's the most direct read out of C. F T our function.

You know that there have been great debate about whether or not there is a ceiling on P. P. F E V. One we can't.

We can't.

Half better than normal lung function right, but in terms of sweat chloride that is how patients are diagnosed with the disease and it is very well understood that if we provide better see FTR.

Reshma Kewalramani: That is a secondary endpoint in the Phase III trial, and that's what we've already studied and reported out in a variety of Phase II trials and it does indeed look to be the case that the Vanza triple is even better than I know, that's a tall order, but it's even better than Trikafta over to you Stuart on. The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

Function benefit that would show up in terms of sweat chloride that is a secondary endpoint in the phase III trial, and that's what we've already studied and reported out in a variety of phase two trials and it does indeed.

Look to be the case that the vans that triple is even better than I know, that's a tall order, but it's even better than try CAFTA over to you Stuart on.

Reshma Kewalramani: Over to you Stuart on the marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

Reshma Kewalramani: Over to you Stuart on the marketplace with that in mind,

Stuart Arbuckle: Yes, so Mike, just as Reshma said on the study, the primary endpoint is non-inferiority versus Trikafta on FEV1, which as we know is an incredibly high bar, but we will be able to see how Vanzacaftor does versus Trikafta in the study, so that's the first thing just to remind you, as Reshma said, we're also looking at measures of superior CFTR function in patients and when we've done research with physicians. Even if the <unk> benefit is the same with vans a catheter. If we can demonstrate improved C. F. T cell function, which is restaurants said the pharmacodynamic measure of that is sweat chloride. There was a lot of enthusiasm from physicians for a product which has that profile. In addition, just to remind you bonds. A catheter is also going to be a once a day. Regimen as well, which is also considered to be a benefit particularly for those patients who have a compliance challenges as well. So we're very much looking forward to the phase III results and think theres going to be if the results come out as we expect them to a high level of enthusiasm prevents the CAFTA. Super helpful. On the Q T that there was a study that's up is that can you say that that was completed in all set. Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard. Ah studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

The marketplace with that in mind, yes, so Mike just as retrofit on the study the primary endpoint is non inferiority versus try catheter on after you warm, which as we know is an incredibly.

Hi, Bob.

But we will be able to see you have answered CAFTA does versus truck. After in the study. So that's the first thing just to remind you as Rushmore said.

Stuart Arbuckle: As Reshma said, we're also looking at measures of superior CFTR function in patients and when we've done research with physicians, even if the FEV1 benefit is the same with Vanzacaftor, if we can demonstrate improved CFTR function, which as Reshma said, the pharmacodynamic measure of that is sweat chloride. There was a lot of enthusiasm from physicians for a product which has that profile. In addition, just to remind you bonds. A catheter is also going to be a once a day. Regimen as well, which is also considered to be a benefit particularly for those patients who have a compliance challenges as well. So we're very much looking forward to the phase III results and think theres going to be if the results come out as we expect them to a high level of enthusiasm prevents the CAFTA. Super helpful. On the Q T that there was a study that's up is that can you say that that was completed in all set. Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard. Ah studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

We're also looking at measures of superior CFT, our function in patients and when we've done research with physicians.

Even if the <unk> benefit is the same with vans a catheter. If we can demonstrate improved C. F. T cell function, which is restaurants said the pharmacodynamic measure of that is sweat chloride. There was a lot of enthusiasm from physicians for a product which has that profile. In addition, just to remind you bonds. A catheter is also going to be a once a day.

Stuart Arbuckle: There was a lot of enthusiasm from physicians for a product which has that profile, in addition, just to remind you, Vanzacaftor is also going to be a once a day regimen as well, which is also considered to be a benefit particularly for those patients who have a compliance challenges as well. So we're very much looking forward to the phase III results and think theres going to be if the results come out as we expect them to a high level of enthusiasm prevents the CAFTA. Super helpful. On the Q T that there was a study that's up is that can you say that that was completed in all set. Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard. Ah studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

Stuart Arbuckle: There was a lot of enthusiasm from physicians for a product which has that profile, in addition just to remind you, Vanzacaftor is also going to be a once a day regimen as well, which is also considered to be a benefit particularly for those patients who have a compliance challenges as well.

Regimen as well, which is also considered to be a benefit particularly for those patients who have a compliance challenges as well. So we're very much looking forward to the phase III results and think theres going to be if the results come out as we expect them to a high level of enthusiasm prevents the CAFTA.

Stuart Arbuckle: So we're very much looking forward to the Phase III results and think there's going to be results come out as we expect them to a high level of enthusiasm for Vanzacaftor. Super helpful. On the Q T that there was a study that's up is that can you say that that was completed in all set. Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard. Ah studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

Stuart Arbuckle: So we're very much looking forward to the Phase III results and think there's going to be results come out as we expect them to a high level of enthusiasm for Vanzacaftor.

Stuart Arbuckle: Super helpful, (inaudible) on the QT that there was a study that's up, is that, can you say that that was completed and all set? Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard. Ah studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

Michael Yee: Super helpful, (inaudible) on the QT that there was a study that's up, is that, can you say that that was completed and all set?

Super helpful.

On the Q T that there was a study that's up is that can you say that that was completed in all set.

Reshma Kewalramani: Yes, nothing new to report there, this is a, the QT is a study we do for a cardiac function, it's one of our standard studies that we do in the clinical pharmacology around. Got it. Thank you next question please check.

Reshma Kewalramani: Yes, nothing new to report there, this is a, the QT is a study we do for a cardiac function, it's one of our standard studies that we do in the clinical pharmacology around.

Yes, nothing new to report there. This is a cute that Q T is a study we do for a cardiac function. It's one of our standard.

Ah studies that we do in the clinical pharmacology around.

Reshma Kewalramani: Got it. Thank you.

Got it. Thank you next question please check.

Operator: The last question will come from Terence Flynn with Morgan Stanley. Please go ahead.

Terence Flynn: Hi, Thanks for taking the questions, I was just wondering if, let's say the theoretical situation, where one of the randomized controlled Phase III acute trials is positive and the other is not, can you still file for approval in that data set or do you need two positive trials and then Stuart I just wondered if you could clarify your comments on 2024 being a foundational year for Exa-cel, You know what that means, is that, does that mean you're comfortable with consensus where it stands or you think it's going to be Somewhat more measured launch, just want to clarify what foundational means, thank you.

24, being a foundational year for extra so.

You know what that means is that does that mean, you're comfortable with consensus where it stands or do you think it's going to be.

Somewhat more measured launch just just want to clarify what foundational means thank you.

Reshma Kewalramani: Yeah Hey Terence this is Reshma, let me comment on acute pain, and then I'll turn it over to Stuart, you know we are very close to having the results from the acute pain program and I'll just leave it at, our goal is to have a positive set of three studies and our goal is to file for a broad moderate to severe acute pain label. Stuart.

Reshma Kewalramani: You know we are very close to having the results from the acute pain program and I'll just leave it at, our goal is to have a positive set of three studies and our goal is to file for a broad moderate to severe acute pain label. Stuart.

Stuart Arbuckle: And on Exa-cel and the comment we made about it being a foundational year, that has nothing to do with consensus, I actually couldn't tell you what consensus is for 2024 for Exa-cel to be perfectly honest with you Terence, it was really a response, we've been asked a lot of questions about what the launch dynamics will look like for extra sell and so we thought it was important to remind people of what the the patient journey is and that is obviously going to begin hopefully. Later this year, when we get regulatory approval and it was really just try to provide some context around that multi stage journey that the patients need to go through. To get extra sell so that was really the reasons for the comment it was responding to questions. We've had about launch dynamics I do want to reiterate something which I said in my prepared remarks as well. Whatever the journey to get there we see this as being a very large commercial opportunity. There are tens of thousands of patients with severe sickle cell disease, and beta thalassemia, who could benefit and despite the the journey being relatively long. This is a journey at the end of the that has the potential for a lifetime of benefit so we feel very optimistic. About the <unk> opportunity and we're looking forward to launching.

The comment we made about it being a foundational year.

Nothing to do with consensus I actually couldn't tell you what consensus is for 2024 for X yourselves to be perfectly honest with you James.

It was really a response, we have been also a lot of questions about what the launch dynamics will look like.

Stuart Arbuckle: We've been asked a lot of questions about what the launch dynamics will look like for Exa-cel and so we thought it was important to remind people of what the patient journey is and that is obviously going to begin hopefully later this year, when we get regulatory approval and it was really just try to provide some context around that multi stage journey that the patients need to go through to get Exa-cel.

For extra sell and so we thought it was important to remind people of what the the patient journey is and that is obviously going to begin hopefully.

Later this year, when we get regulatory approval and it was really just try to provide some context around that multi stage journey that patients need to go through.

To get extra sell so that was really the reasons for the comment it was responding to questions. We've had about launch dynamics I do want to reiterate something which I said in my prepared remarks as well.

Stuart Arbuckle: So that was really the reasons for the comment, it was responding to questions we've had about launch dynamics, I do want to reiterate something which I said in my prepared remarks as well, whatever the journey to get there, we see this as being a very large commercial opportunity, there are tens of thousands of patients with severe sickle cell disease, and beta thalassemia, who could benefit and despite the journey being relatively long, this is a journey at the end of it that has the potential for a lifetime of benefit so we feel very optimistic about the Exa-cel opportunity and we're looking forward to launching.

Whatever the journey to get there we see this as being a very large commercial opportunity. There are tens of thousands of patients with severe sickle cell disease, and beta thalassemia, who could benefit and despite the the journey being relatively long. This is a journey at the end of the that has the potential for a lifetime of benefit so we feel very optimistic.

About the <unk> opportunity and we're looking forward to launching.

Susie Lisa: Thanks, Chuck if you can give the details please for callbacks

Operator: Yes, ma'am a replay of today's event will be available shortly after the call concludes by dialing 18773447529 or 14123170088 using the replay access code 2047491, the conference has now concluded, thank you for attending today's presentation you may now disconnect.

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

[music].

Yes.

Yeah.

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