Q1 2022 Vertex Pharmaceuticals Inc Earnings Call

Michael Partridge: Good evening. This is Michael Partridge.

Good evening. This is Michael Partridge, welcome to vertex as first quarter 2022 financial results Conference call.

Unknown Executive: Welcome to Vertex's first quarter 2022 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Operating Officer, and Charlie Wagner, Chief Financial Officer. Dr. Bastian Osana, Chief of Vertex Cell and Genetic Therapies, and Dr. David Altshuler, Chief Scientific Officer, will join for Q&A. We recommend that you access the webcast slides as you listen to this call. This call is being recorded, and a replay will be available on our website.

On tonight's call, making prepared remarks, we have Dr. Rachel Mckay, while Rahmani for Texas, CEO , and President Stuart Arbuckle, Chief operating Officer, and Charlie Wagner, Chief Financial Officer, Dr. Bastian, Lassana chief of vertex cell and genetic therapies and Dr. David Altshuler, Chief Scientific officer will join for Q&A.

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

Unknown Executive: 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's marketed CF medicines, our pipeline, and Vertex's future financial performance, are based on management's current assumptions, while actual outcomes and events could differ materially.

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 CF 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, we will review on the call. This evening, our non-GAAP I will now turn the call over to Dr rushed vacate while rahmani.

Unknown Executive: I would also note that select financial results and guidance we will review on the call this evening are non-GAAP. I will now turn the call over to Dr. Reshma Kewalramani. Thanks, Michael.

Reshma Kewalramani: Before we begin, as this will be Michael Partridge's last quarterly call with us, I'd like to take a moment to recognize Michael for his outstanding service and contributions to Vertex. For 25 years, he's been the face of Vertex to analysts and investors, and with his calm and steady approach, he has led our IR team through countless milestones and many evolutions of the company. More recently, through the launch of all four of our marketed cystic fibrosis medicines and the emergence of our broad mid and late stage pipeline, Michael has been an integral part of the Vertex leadership team, helping share our story with the world. He has shown a true passion for Vertex and the patients we serve. We are grateful for his dedication.

Thanks, Michael before we begin as this will be Michael Partridge, just last quarterly call with that I'd like to take a moment to recognize Michael for his outstanding service and contributions to vertex for 25 years, he's been the face of vertex with analysts and investors and with his calm and steady approach Michael his letter.

IR team through countless milestones and many evolutions of the company more recently through the launch of all four of our marketed cystic fibrosis medicines and the emergence of I broad mid and late stage pipeline. Michael has been an integral part of the vertex leadership team, helping share our story with the world.

Michael has shown a true passion for vertex and the patients. We serve we are grateful for his dedication and I want to personally thank Michael for all that he has done for vertex.

Reshma Kewalramani: And I want to personally thank Michael for all that he has done for Vertex. Now, on to the quarterly review. Vertex is off to an excellent start across the board, with strong performance in the CF business, rapid advancement of the pipeline, and continued operational excellence. In Q1, CF product revenues grew 22% year-on-year to $2.1 billion, reflecting continued growth in the number of CF patients treated globally. And despite continued significant investment in internal and external innovation, our non-gap operating margins remained industry leading at 56%.

Onto the quarterly review.

Vertex is off to an excellent start across the board with strong performance in the CF business rapid advancement of the pipeline and continued operational excellence Q1, CF product revenues grew 22% year on year to $2 1 billion, reflecting continued growth in the number of CF patients treated globally.

And despite continued significant investments in internal and external innovation, our non-GAAP operating margins remained industry, leading at 56% we maintained a rapid pace of progress in research and across the clinical stage pipeline with a half a dozen programs now post the POC stage.

Reshma Kewalramani: We maintained a rapid pace of progress in research and across the clinical stage pipeline, with a half a dozen programs now past the POC stage. And we finished the quarter with a strong balance sheet and $8.2 billion in cash and investments.

And we finished the quarter with a strong balance sheet and $8 2 billion in cash and investments.

Reshma Kewalramani: CF has been the exemplar of our R&D strategy. However, the last six to 12 months have made it clear that our R&D strategy is proving itself beyond CF with the discovery and development of small molecules and cell and genetic therapies across a number of disease areas. This serial innovation enables the potential to transform, if not cure, multiple diseases and, in so doing, help more patients and drive long-term growth for the company. Fundamentally, the goal of our strategy, grounded in causal human biology, validated targets, and biomarkers that translate from bench to bench side and all the way through pivotal development, is to increase the odds of success in drug discovery and development. With the data we've generated in CF, in sickle cell disease, and beta thalassemia, and now, in rapid succession, with positive proof of concept in APOL1-mediated kidney disease.

So yes, it's been the exemplar of our R&D strategy. The last six to 12 months and made it clear our R&D strategy is proving itself beyond CF with the discovery and developing a small molecules and cell and genetic therapies across a number of disease areas. This serial innovation enables the potential to transform its not Q.

Sure multiple diseases and in so doing help more patients and drive long term growth for the company.

I'm mentally the goal of our strategy grounded in causal human biology validated targets and biomarkers that translate from bench to bedside and all the way through pivotal development is to increase the odds of success in drug discovery and development with the data we've generated in CF in sickle cell disease and Bayer.

South senior and now in rapid succession with positive proof of concept in April one mediated kidney disease.

Reshma Kewalramani: Since Pain and Type 1 Diabetes, our clinical stage pipeline has never been broader in terms of the number of disease areas, more diverse in terms of modalities, or more advanced. The company is now at a new inflection point with continued growth in CF, the advancement of our broad clinical pipeline with six programs in mid and late stage development representing multi-billion dollar opportunities, and the potential of the next wave of therapies approaching the clinic.

Pain and type one diabetes, our clinical stage pipeline has never been broader in terms of the number of disease areas more diverse in terms of modalities or more advanced.

The company is now at a new inflection point with continued growth in CF, the advancement of a broad clinical pipeline with six programs in mid and late stage development, representing multi billion dollar opportunities and the potential from the next wave of therapies approaching the clinic in this next group of programs that have initiated I D.

Reshma Kewalramani: In this next group of programs that have initiated IND enabling studies are our mRNA program in CF, the cells plus device program in type one diabetes, the next wave of small molecule correctors in AATD, and our in vivo gene editing program in DMD.

Enabling studies is our mrna program in CF, the South plus device program in type one diabetes. The next wave of small molecule corrector and a a T D and our in vivo gene editing program in D. M D. A.

Reshma Kewalramani: A number of these programs are on track for IND filings later this year, with clinical trials beginning thereafter. Our R&D strategy, combined with our business model, positions us well for continued innovation and sustained growth as we work to bring additional transformative medicines to more patients around the globe. With this as context, I'll now review the R&D highlights for the quarter. Looking to our future in CF, we continue to strengthen our leadership for the long term.

A number of these programs are on track for I N. D filings later this year with clinical trials beginning thereafter.

Our R&D strategy combined with our business model positions us well for continued innovation and sustained growth as we work to bring additional transformative medicines to more patients around the globe with this as context I'll now review the R&D highlights for the quarter.

Looking to our future in CF, we continued to strengthen our leadership for the long term a real world experience with truck after continues to accumulate and as Stuart will discuss raises the bar for any regimens in development that said if it is possible to outperform try character were determined to be the ones, who do so our next <unk>.

Reshma Kewalramani: Our real-world experience with Trikafta continues to accumulate, and as Stuart will discuss, raises the bar for any regimens in development. That said, if it is possible to outperform Trikafta, we're determined to be the ones who do so.

Reshma Kewalramani: Our next-in-class triple combination of VX1-2-1 Tezukafta 5-6-1 is rapidly progressing through pivotal development. More than 180 clinical trial sites are open and enrolling patients in our Skyline Phase III program. We expect to complete enrollment by late 2022 or early 2023. As a reminder, VX1-2-1 Tezukafta 5-6-1 has the potential for greater clinical benefit than Trikafta and is a more convenient once-daily treatment that carries a lower royalty obligation for Vertex. For the more than 5,000 patients who do not make any CFTR protein and cannot benefit, therefore, from a CFTR modulator, we are developing an mRNA therapy together with our partner, Moderna.

Triple combination of VX 121, Tezak. After 561 is rapidly progressing through pivotal development more than 180 clinical trial sites are open and enrolling patients in our skyline Phase III program, we expect to complete enrollment by late 2022 or early 'twenty 'twenty three as a reminder, the X one too.

One test a capped a 561 has the potential for greater clinical benefit than try CAFTA and has a more convenient once daily treatment that carries a lower royalty obligation for vertex for the more than 5000 patients who do not make any C. F. T F protein and cannot benefit therefore from a C. F. T. R. Modulator, we are developing an MRI.

In a therapy together with our partner Madonna I N D. Enabling studies for this program have been completed and we remain on track to submit a 90 in the second half of 2022 with clinical development starting thereafter.

Reshma Kewalramani: IND-enabling studies for this program have been completed, and we remain on track to submit an IND in the second half of 2022, with clinical development starting thereafter. Moving beyond CF, starting with CTX001, our gene editing approach designed to provide a potential functional cure for sickle cell disease and beta thalassemia.

Turning to the pipeline beyond CF, starting with C. T X years here, one our gene editing approach designed to provide a potential functional cure for sickle cell disease and beta thalassemia, we plan to submit for U S and EU regulatory approvals for C. T X series, you're one for beta thalassemia and sickle cell disease.

Reshma Kewalramani: We plan to submit for US and EU regulatory approvals for CTX001 for beta thalassemia and sickle cell disease by the end of 2022, and we expect this to be our next commercial launch. Enrollment in both phase 3 studies is complete, and we have now dosed more than 75 patients across both programs. We look forward to sharing more clinical data on CTX001, including longer-term follow-up and more patients at medical forums this year.

At the end of 2022 and we expect this to be our next commercial launch enrollment in both phase III studies is complete and we have now dosed more than 75 patients across both programs. We look forward to sharing more clinical data on C. T X years, you're one including longer term follow up and more patients and medical forums. This year.

Moving on to the X 147, our first in class small molecule inhibitor for people with April one mediated kidney disease or a M. K D, which has made rapid progress into pivotal development in December we reported unprecedented phase II proof of concept results in patients with the F. S. G. S. A particular kind of eight.

Reshma Kewalramani: Moving on to VX147, our first-in-class small molecule inhibitor for people with APOL1-mediated kidney disease, or AMKD, which has made rapid progress into pivotal development. In December, we reported unprecedented Phase II proof-of-concept results. In patients with FSGS, a particular kind of APOL1-mediated kidney disease, treatment with VX147 led to a 47.6% reduction in proteinuria compared to baseline. VX147 was generally well-tolerated. There were no SAEs related to VX147, and all AEs were mild to moderate in severity.

Paul one mediated kidney disease treatment with VX 147 led to a 47, 6% reduction in proteinuria compared to baseline VX 147 was generally well tolerated. There were no SAE is related to be X 147, and all aes were mild to moderate in severity in.

Reshma Kewalramani: In late March, we initiated pivotal development of VX147 following agreement with FDA and the design of the program, which included one, a single adaptive phase two, three study design in people with two ApoL1 mutations, pertinuria, and decreased renal function. Two, evaluation of VX147 in the broad AMKD population, representing approximately 100,000 people in the US and Europe with this disease. And three, the ability to conduct an interim analysis, which, if positive, could provide a pathway to accelerated approval in the US.

In late March we initiated pivotal development of VX 147, following agreement with F. D. A N. The design of the program, which included one a single adaptive phase two three study design in people with two April one mutations proteinuria and decrease renal function to evaluation of VX 147.

And the broad a M. Katie population, representing approximately 100000 people in the U S and Europe with this disease and.

And three the ability to conduct an interim analysis, which if positive could provide a pathway to accelerated approval in the U S.

Reshma Kewalramani: Transitioning now to our pain program. In late March, we announced that VX548, a novel, first-in-class, non-opioid, NAV1.8 inhibitor, achieved statistically significant and clinically meaningful relief in two Phase II studies of acute pain, meeting our high expectations. In the two studies, one following abdominoplasty and one following bunionectomy, VX548 at the highest dose tested showed a rapid, sustained, and consistent decrease in pain intensity compared to placebo on the primary endpoint of SPID48, a time-weighted sum of the pain intensity difference from time of first dose to 48 hours.

Transitioning now to our pain program.

In late March we announced that VX 548, a novel first in class non opioid NAV, one eight inhibitor achieved statistically significant and clinically meaningful relief in two phase II studies of acute pain meeting our high expectations in the two studies one following abdominoplasty and one following bunionectomy.

Me VX 548 at the highest dose tested showed a rapid sustained and consistent decrease in pain intensity compared to placebo on the primary endpoint of speed 48, a time weighted some of the pain intensity difference from time of first dose to 48 hours.

Reshma Kewalramani: In assessing the SPID-48 score, it's important to note higher scores indicate greater pain relief. VX548 was superior to placebo with a statistically significant mean SPID48 score of 37.8 in abdominoplasty and 36.8 in bunionectomy. In the reference arm of the study, standard of care opioid therapy showed a mean SPID48 difference from placebo of 12.5 and 14.7, respectively. From a safety and tolerability perspective, VX548 was well-tolerated at all doses. There were no serious adverse events related to VX548, and the majority of adverse events were mild or moderate.

In assessing the spend 48 score it's important to note higher scores indicate greater pain relief.

X five four it was superior to placebo with a statistically significant mean spend 48 of 37.8, an abdominoplasty and 36.8 in Bunionectomy in the reference arm of the study standard of care opioid therapy showed a mean spend 48 difference from placebo of 12.5.

Five and $14 seven respectively.

From a safety and Tolerability perspective, the X five four it was well tolerated at all doses there were no serious adverse events related to VX 548, and the majority of adverse events were mild or moderate.

Reshma Kewalramani: Given the high unmet need for an efficacious and well-tolerated non-opioid pain medicine, we are working with urgency to advance VX548. Our goal is to bring forward a new class of pain treatment with the potential to provide effective pain relief without the addictive potential or adverse side effects of opioids. We plan to advance VX548 into pivotal development for acute pain in the second half of 2022, pending discussions with regulators. I'll conclude with the Type 1 Diabetes Program and VX880, our stem cell-derived, fully differentiated, islet cell replacement therapy that could offer a functional cure for people living with Type 1 Diabetes. In the U.S. and Europe alone, Type 1 diabetes affects more than 2.5 million people.

Given the high unmet need for an efficacious and well tolerated non opioid pain medicine, we are working with urgency to advance VX 548. Our goal is to bring forward a novel class of pain treatment with the potential to provide effective pain relief without the addictive potential or adverse side effects of opioids.

We plan to advance VX five forayed into pivotal development for acute pain in the second half of 2022 pending discussions with regulators.

I'll conclude with the type one diabetes program and VX 880, our stem cell derived fully differentiated islet cell replacement therapy that could offer a functional cure for people living with type one diabetes in the U S and Europe alone type one diabetes affects more than 2.5 million people.

Reshma Kewalramani: As we announced earlier this week, the VX-880 program has been placed on clinical hold in the U.S. by the FDA, and we're working with urgency to understand more. At that time, we also shared the safety and efficacy data from the first three patients treated to date. To recap, the first patient who was treated with half the target dose of cells achieved insulin independence at day 270 with a hemoglobin A1C level of 5.2%.

As we announced earlier this week. The VX 880 program has been placed on clinical hold in the U S. By the F D. A and were working with urgency to understand more.

At that time, we also shared the safety and efficacy data from the first three patients treated to date.

To recap the first patient who was treated with half the target dose of cells has achieved insulin independence at day 270, with a hemoglobin a one C level of 5.2%. The second patient also would have dose had positive results through day 150, the patient achieved robust.

Reshma Kewalramani: The second patient, also on a half dose, had positive results through day 150. The patient achieved robust increases in measures of pancreatic islet cell function and improved glucose control while simultaneously experiencing a 30% decrease in exogenous insulin use.

Increases in measures of pancreatic islet cell function and improved glucose control, while simultaneously experiencing a 30% decrease in exogenous insulin use taken together the results from patients one and patients to both treaty that half dose demonstrate proof of concept for VX 880.

Reshma Kewalramani: Taken together, the results from patients one and two, both treated at half doses, demonstrate proof of concept for VX880. The third patient, who is the first to receive a full dose of VX-880, has reached the Day 29 milestone. As of Day 29, the patient showed encouraging early indications of efficacy, with increasing C-peptide levels and improving glycemic control. The first detailed assessment of pancreatic islet function and glycemic control for patients in the study occurred at the day 90 visit.

The third patient who was the first to receive a full dose of VX 880 has reached the day 29 milestone as of day 29, the patient showed encouraging early indications of efficacy with increasing C peptide levels and improving glycemic control.

The first detailed assessment of pancreatic islet function and glycemic control for patients in the study occurs at the day 90 visit.

Reshma Kewalramani: Across the program, in the three patients dosed to date, there have been no SAEs related to VX880. The majority of adverse events are mild to moderate, and the overall safety profile is consistent with the immunosuppressive regimen used in the study and the perioperative period. These are the data to date.

Across the program in the three patients dosed to date there are no S. H E related to VX 880, the majority of adverse events are mild to moderate and the overall safety profile was consistent with the immunosuppressive regimen used in the study and the perioperative period.

Reshma Kewalramani: Of course, all three patients will continue to be followed per study protocol. We look forward to working constructively and expeditiously with the FDA to understand and address their questions so that we can resume the trial as soon as possible in the U.S. To close out on Type 1 Diabetes, a quick word on our Cells Plus Device program. We continue to make progress with our cells and device approach. In this program, instead of using immunosuppression to protect cells from the immune system, the immunoprotective device is designed to serve that function.

These are the data to date of course, all three patients will be continued to be followed per study protocol. We look forward to working constructively and expeditiously with the F D a to understand and address their questions. So that we can resume the trial as soon as possible in the U S to close.

Add on type one diabetes, a quick word on our south plus device program, we continue to make progress with ourselves and device approach in this program instead of using immuno suppression to protect the cells from the immune system. The immuno protective device is designed to serve that function. We remain on track for 90 filing for this program later.

Stuart Arbuckle: We remain on track for an IND filing for this program later this year. In summary, Vertex continues to deliver significant growth in CF. We're making rapid progress with programs in six disease areas in mid and late stage development, including five programs that are already in or entering pivotal development, with another wave of programs on track to enter the clinic starting later this year. We have a strong financial profile and balance sheet that enables continued investment to drive serial innovation. With that, I'll turn it over to Stuart. Thanks, Reshma.

This year.

In summary, vertex continues to deliver significant growth in CF, we're making rapid progress with programs in six disease areas in mid and late stage development, including five programs that are already in or entering pivotal development with another wave of programs on track to.

Enter the clinic starting later this year, we have a strong financial profile and balance sheet that enables continued investment to drive serial innovation with that I'll turn it over to Stuart.

Stuart Arbuckle: I'm pleased to review tonight our continued strong commercial performance in CF and our clear path towards future growth in CF and our plans for expansion into additional disease areas. Vertex's CF business continues to grow at a rapid pace, driven by consistent performance of Trikafta in the U.S. and the continued robust uptake of Trikafta CaffeTrio outside the U.S., following significant reimbursement progress internationally over the past year. Q1 CF product revenue of $2.1 billion grew 22% year over year as more patients have come on therapy.

Thanks, Rushmore I'm pleased to review Tonight, our continued strong commercial performance in CF.

Clear path towards future growth in C F and our plans for expansion into additional disease areas.

Vertex is CF business continues to grow at a rapid pace driven by consistent performance of truck after in the U S and the continued robust uptake of Tri Caf to Caf trio outside the U S. Following significant reimbursement progress internationally over the past year.

Q1, CF product revenue of $2.1 billion grew 22% year over year as more patients have come on therapy U S revenues grew 9% to $1.37 billion in the first quarter of 2022, driven by additional patients starting treatment with Tri CAFTA, most notably children ages six to 11.

Stuart Arbuckle: U.S. revenues grew 9% to $1.37 billion in the first quarter of 2022, driven by additional patients starting treatment with Trikafta, most notably children ages 6 to 11, following the mid-2021 approval. Revenue outside the U.S. increased 55% over the first quarter of 2021 to $729 million, driven by rapid uptake of Trikafta-Caftreo in countries where we reached reimbursement agreements. We started the year with more than 25,000 patients in North America, Europe, and Australia who could benefit from a CFTR modulator but were not yet on therapy. These patients fell primarily into one of three categories.

Following the mid 2021 approval revenue outside the U S increased 55% over the first quarter of 2000 $21 million to $729 million driven by rapid uptake of Tri Caf to Caf trio in countries, where we reached reimbursement agreements we started the year with more than 25000 patients in north.

Erica Europe , and Australia, who could benefit from a C. F T R modulator, but we're not yet on therapy. These.

These patients fell primarily into one of three categories, one patients who have not yet initiated treatment largely in countries, where we are recently reimbursed and therefore early in the launch curve to patients in geographies, where we are not yet reimbursed and three younger age groups, who will be addressed through ongoing label expansions.

Stuart Arbuckle: One, patients who have not yet initiated treatment, largely in countries where we are recently reimbursed and therefore are early in the launch curve. Two, patients in geographies where we are not yet reimbursed. And three, younger age groups who will be addressed through ongoing label expansions.

Stuart Arbuckle: We are confident in our ability to reach the vast majority of these patients over time. TRIKAFTA-CAF TRIO is now available and reimbursed in more than 25 countries. We have continued to reach new reimbursement agreements, with the most notable recent example being Australia, where TRIKAFTA is now reimbursed for eligible patients ages 12 and above. We also continue to make progress extending treatment to younger patients. In January, we secured approval for Caftreo in Europe and the UK for children ages 6 to 11.

We are confident in our ability to reach the vast majority of these patients over time truck. After Caf trio are now available and reimbursed in more than 25 countries. We have continued to reach new reimbursement agreements with the most notable reached example, being Australia, where try CAFTA is now reimbursed for eligible patients ages 12 and above.

We also continue to make progress extending treatment to younger patients in January we secured approval for capturing in Europe , and the U K for children Ages six to 11 and in April Health, Canada granted marketing authorization for Tri CAFTA for the same patients in the U S. We recently submitted an S N D a for approval of OCA.

Stuart Arbuckle: And in April, Health Canada granted marketing authorization for Trikafta for the same patients. In the US, we recently submitted an SNDA for approval of Orkambi for children ages 1 to less than 2 years. We have also completed enrollment in the Phase 3 study of Trikafta in children ages 2 to 5, and we anticipate submitting for US approval for this age group before the end of 2022. As Reshma mentioned, powerful real-world and long-term experience with Trikafta further strengthens the clinical value proposition of this combination.

B for children ages, one to less than two years. We also completed enrollment in the phase III study of Tri CAFTA in children ages, two to five and anticipate submitting for U S approval for this age group before the end of 2022, as Rushmore mentioned powerful real world and long term experience with Tri CAFTA furthest.

<unk> the clinical value proposition of this combination we have previously shown evidence that treatment with our medicines kalydeco or Cambrian simpatico slows lung function decline one of the hallmarks of disease progression for CF patients. We now have data that compares lung function over time for patients treated with Tri CAFTA too.

Stuart Arbuckle: We have previously shown evidence that treatment with our medicines, Kalydeco, Orkambi, and Symdeco, slows lung function decline, one of the hallmarks of disease progression for CF patients. We now have data that compares lung function over time for patients treated with Trikafta to untreated matched controls. And these data show that patients on Trikafta, on average, do not lose any lung function over a two-year follow-up period. Generally, CF patients lose one to three percent of lung function every year.

Untreated matched controls and these data show that patients on Tri CAFTA on average do not lose any lung function over a two year follow up period generally CF patients lose 1% to 3% of lung function every year, we will be presenting these important new data at an upcoming medical forum.

Stuart Arbuckle: We will be presenting these important new data at an upcoming medical forum. As Reshma noted, the last 6-12 months have been a remarkable period for Vertex, as multiple programs reached late-stage development. I would like to provide a few thoughts on two programs in late-stage development that could be among our next commercial opportunities. Starting with CTX001, our CRISPR-Cas9-based gene editing therapy for hemoglobinopathies, which we plan to file for regulatory approval before the end of this year. Commercial and launch preparation activities for sickle cell disease and beta thalassemia are well underway.

Freshman noted the last six to 12 months have been a remarkable period for vertex as multiple programs reached late stage development I would like to provide a few thoughts on two programs in late stage development that could be among our next commercial opportunities starting with CTX 001, or CRISPR Cas nine based gene editing.

Therapy for hemoglobin, all parties, which we plan to file for regulatory approval before the end of this year commercial and launch preparation activities for sickle cell disease, and beta thalassemia are well underway over the past year, we have developed a deep understanding of the sickle cell and T D T markets, including where patients with these diseases are.

Stuart Arbuckle: Over the past year, we have developed a deep understanding of the sickle cell and TDT markets, including where patients with these diseases are concentrated, the physicians who would refer them for treatment, and the key treatment centers that will facilitate the patient journey. With our submissions planned for later this year, our launch preparation activities are progressing rapidly. Key leadership positions and teams are in place across multiple functions, including medical, commercial, and manufacturing.

Rated the physicians, who would refer them for treatment and the key treatment centers that will facilitate the patient journey with our submissions planned for later this year. Our launch preparation activities are progressing rapidly key leadership positions and teams are in place across multiple functions, including medical commercial and manufacturing.

Stuart Arbuckle: A small number of centers of excellence in the US and Europe will treat the vast majority of severe sickle cell and thalassemia patients. Our research suggests that about 90% of U.S. patients reside in 24 states, and about 75% of patients in Europe reside in four countries. We have identified potential centers and their referral networks in these countries.

Small number of centers of excellence in the U S and Europe will treat the vast majority of severe sickle cell and thalassemia patients. Our research suggests that about 90% of U S patients reside in 24 states and about 75% of patients in Europe reside in four countries, we have identified the potential centers and their referral net.

Works in these countries, we are already engaging with public and commercial payors in the U S and EU and we are developing robust patient service programs to support patients throughout their treatment journey, we continue to see tremendous potential for CTX 001 to help patients and we look forward to the possibility of bringing this groundbreaking therapy.

Stuart Arbuckle: We are already engaging with public and commercial payers in the U.S. and E.U., and we are developing robust patient service programs to support patients throughout the treatment journey. We continue to see tremendous potential for CTX001 to help patients, and we look forward to the possibility of bringing this groundbreaking therapy to those living with sickle cell disease and beta thalassemia. Finally, with the recent completion of the two phase two studies in acute pain and the positive POC results in both studies, as Reshma noted, we now plan to advance VX548 into pivotal development in acute pain in the second half of this year.

<unk> to those living with sickle cell disease, and beta thalassemia finally, with the recent completion of the two phase III studies in acute pain and the positive P. O C results in both studies as Rushmore noted, we now plan to advance VX 548 into pivotal development in acute pain in the second half of this year, Let me review with you.

Stuart Arbuckle: Let me briefly review with you the market opportunity we see in pain. There is a vast unmet need for the treatment of moderate to severe pain, and especially for medicines with an improved benefit-risk profile, including avoiding the side effects and addictive qualities of standard of care opioids. To give you some perspective on the market for acute pain, which is our initial target market for VX548, every year there are more than 1.5 billion treatment days for acute pain in the US, with a large proportion of these including prescribed opioids.

<unk> the market opportunity, we see in pain, there is a vast unmet need in the treatment of moderate to severe pain, and especially for medicines with an improved benefit risk profile, including avoiding the side effects and addictive qualities of standard of care opioids to give you some perspective on the market for acute pain, which is our initial trial.

Get market for VX five four right every year there are more than 1.5 billion treatment days for acute pain in the U S with a large proportion of these including a prescribed opioid.

Stuart Arbuckle: It is an unfortunate fact that some of these scripts result in addiction problems for some patients and contribute to the opioid epidemic in the US. Provisional data from the CDC's National Center for Health Statistics for the latest 12-month period ending April 2021 estimated that there were more than 75,000 overdose deaths from opioids in the US, an increase of 35% compared to the prior 12-month period.

It is an unfortunate fact that some of these scripts, resulting addiction problems for some patients and contribute to the opioid epidemic in the U S. Provisional data from the Cdc's National Center for Health Statistics for the latest 12 month period, ending April 2021 recently estimated that there were more than 75000 overdose deaths from oak.

<unk> in the U S an increase of 35% compared to the prior 12 month period.

Stuart Arbuckle: A novel, highly effective class of medicines that does not have these safety concerns would therefore have tremendous potential. For instance, one can imagine a step therapy paradigm in which a patient is started on NSAIDs, escalated to a NAV1.8 inhibitor, and only as a last resort, prescribed an opioid. The first indication we are pursuing for VX548 is moderate to severe acute pain, and we see this segment of the market as a specialty market that fits the vertex commercialization model well. But the mechanism is applicable to other types of pain, as demonstrated by VX150, which showed positive POC across acute, neuropathic, and musculoskeletal pain.

Our novel highly effective class of medicines that does not have these safety concerns would therefore have tremendous potential for instance, one can imagine a step therapy paradigm in which a patient has started on nsaids escalated to a NAV one eight inhibitor and only as a last resort prescribed an opioid the first indication we are pursuing for.

X 548 is moderate to severe acute pain and we see this segment of the market as a specialty market that fits the vertex commercialization model well.

But the mechanism is applicable to other types of pain as demonstrated by VX 150, which showed positive P O C across acute neuropathy and musculoskeletal pain.

Stuart Arbuckle: We look forward to discussing plans for these indications on future calls. I am very excited about our continued progress in bringing our CF medicines to more patients globally and about the promise of our late-stage pipeline. I will now turn the call over to Charlie. Thanks, Stuart. Vertex is off to an excellent start in 2022, as our R&D pipeline continued to deliver significant milestones, and we again delivered strong financial performance in the first quarter. First quarter total product revenues were $2.1 billion, an increase of 22% compared to the first quarter of 2021.

We look forward to discussing plans in these indications on future calls.

I am very excited about our continued progress in bringing our CF medicines to more patients globally and about the promise of our late stage pipeline I will now turn the call over to Charlie.

Thanks, Stuart vertex is off to an excellent start in 2020 two as our R&D pipeline continued to deliver significant milestones and we again delivered strong financial performance in the first quarter first quarter total product revenues were $2 1 billion, an increase of 22% compared to the first quarter of 2021 our growth was again.

Charlie Wagner: Our growth was again primarily driven by new patients coming on therapy compared to the prior year, including continued robust uptake of Caftrio internationally following expanded reimbursement and access in a number of geographies over the past year, as well as continued growth of Trikafta in the U.S. In our first quarter 2022, combined non-GAAP R&D and SG&A expenses were $687 million, compared to $531 million in Q The year-over-year increase in expenses was driven by increased research costs and investments in our advancing pipeline, with multiple programs now in mid- and late-stage development.

Primarily driven by new patients coming on therapy compared to the prior year, including continued robust uptake of Caf trio internationally following expanded reimbursement access in a number of geographies over the past year as well as continued growth of trade catheter in the U S. Our first quarter 2022 combined non-GAAP R&D and SG&A expenses were.

687 million compared to 531 million in Q1, 2021 the year over year increase in expenses was driven by increased research costs and investments in our advancing pipeline with multiple programs now in mid and late stage development. Additionally, we continue to make investments in CTX, Oh, one pre commercial activities in anticipation.

Charlie Wagner: Additionally, we continue to make investments in CTX-001 pre-commercial activities in anticipation of regulatory filing by the end of this year. Starting in the first quarter of 2022 and going forward, consistent with reporting practices that have recently been adopted by peer companies, we no longer exclude from our non-GAAP results research and development charges from upfront or contingent milestone payments in connection with collaborations, asset acquisitions, or the licensing of third-party IP. We have also updated prior-year reported non-GAAP figures to be consistent with the new basis of presentation.

As a patient a regulatory filing by the end of this year starting in the first quarter of 2022 and going forward consistent with reporting practices that have been recently adopted by peer companies, we no longer exclude from our non-GAAP results research and development charges from upfront or contingent milestone payments in connection with collaborations asset acquisitions or the license.

Singh of third party IP, we have also updated prior year reported non-GAAP figures to be consistent with the new basis of presentation.

Charlie Wagner: This change in reporting affects only our non-GAAP numbers, and the impacts on reported results for Q1-22 and Q1-21 were not material. Our continued strong revenue growth, combined with our efficient operating model, resulted in a Q1 non-GAAP operating margin of 56% and non-GAAP operating income of $1.17 billion, an increase of 16% year-over-year. Our non-GAAP effective tax rate for the first quarter of 20

This change in reporting affects only or non-GAAP numbers and the impacts on our reported results for Q1, 'twenty two and Q1 'twenty one were not material. Our continued strong revenue growth combined with our efficient operating model resulted in Q1, non-GAAP operating margin of 56% and non-GAAP operating income of 1.17 billion.

An increase of 16% year over year.

Our non-GAAP effective tax rate for the first quarter of 2022 was 22% we ended the quarter with $8 2 billion in cash and short term investments as we continue to maintain a very strong balance sheet profile now to guidance.

Charlie Wagner: We ended the quarter with $8.2 billion in cash and short-term investments as we continue to maintain a very strong balance sheet profile. Now to guidance. We are maintaining our previously issued guidance for full year 2022 CF product revenue and non-GAAP effective tax rate. However, we are adjusting our guidance for combined non-GAAP R&D and SG&A expenses to reflect the change in reporting of upfronts and milestones as I described moments ago. Specifically, our guidance for total CF product revenue remains at 8.4 to 8.6 billion.

Charlie Wagner: At the midpoint, this is a year-over-year increase of approximately 1 billion, or 12% growth. Non-GAAP operating expenses are now projected in a range of $2.82 to $2.92 billion, including potential upfront and milestone payments from existing or ongoing collaborations. Finally, we continue to project a non-GAAP effective tax rate in a range of 21 to 22 percent.

We are maintaining our previously issued guidance for full year 2022 CF product revenue and non-GAAP effective tax rate, we are adjusting our guidance for combined non-GAAP R&D and SG&A expenses to reflect the change in reporting of Upfronts and milestones as I described moments ago, specifically our guidance for total CF.

Product revenue remains at 8.4 to 8.6 billion at.

At the midpoint. This is a year over year increase of approximately 1 billion or 12% growth.

non-GAAP operating expenses are now projected in a range of 2.82 to 2.92 billion, including potential upfront and milestone payments from existing or ongoing collaborations.

Finally, we continue to project a non-GAAP effective tax rate in a range of 21% to 22%.

Charlie Wagner: As we look out to the remainder of the year and into 2023, we have a number of important pipeline milestones that will demonstrate our continued progress, and these are shown on slide 16 of the webcast. In summary, we are on track for our eighth consecutive year of double-digit revenue growth in 2022. The CF business is strong, and we have invested to maintain leadership in CF for the long term.

As we look out to the remainder of the year and into 'twenty 'twenty. Three we have a number of important pipeline milestones that will demonstrate our continued progress and these are shown on slide 16 of the webcast. In summary, we are on track for our eighth consecutive year of double digit revenue growth in 2022 the CF business is strong and we have invested to maintain leadership in CF.

For the long term at the same time, we are now going through an inflection point as a company well on our way to diversifying vertex into new disease areas beyond CF is the broad pipeline of potentially transformative medicines advances as a result, our unique business strategy, which enables significant reinvestment in internal and external innovation.

Charlie Wagner: At the same time, we are now going through an inflection point as a company, well on our way to diversifying Vertex into new disease areas beyond CF as the broad pipeline of potentially transformative medicines advances. As a result, our unique business strategy, which enables significant reinvestment in internal and external innovation, while sustaining high profitability, leaves us exceptionally well positioned for further significant value creation over time. We look forward to updating you further as we progress through the year.

While sustaining high profitability leaves us exceptionally well positioned for further significant value creation over time, we look forward to updating you further as we progress through the year, let's now open the call to questions.

Charlie Wagner: Let's now open the call to questions. Thank you. We will now begin the question and answer session. To ask a question, you may press star then 1 on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the key.

Thank you we will now begin the question and answer session.

To ask a question you May Press Star then one on your Touchtone phone.

If youre using a speakerphone please pick up your handset before pressing the keys.

Unknown Executive: And to withdraw your question, please press the star then. And at this time, we'll pause momentarily to assemble our roster. And the first question will come from Corey Kasimov with J.P. Morgan. Please go ahead. Good afternoon.

And Swift draw. 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 Cory cast them off with J P. Morgan. Please go ahead.

Great. Good afternoon, just want to say thanks to Michael first of all for all his help over the years. It's obviously been very much appreciated. So my question is on your phase III trial for VX 147, and M. Katy and I'm curious about your kind of your confidence in the potential for an accelerated filing at the 48 week time point.

Unknown Executive: I just want to say thanks to Michael, first of all, for all his help over the years. It's obviously been very much appreciated. So my question is about your phase three trial for VX147 and AMKD, and I'm curious about your confidence in the potential for an accelerated filing at the 48 week time point based on the predictive nature of reduction in proteinuria materially impacting the slope of EGFR curves at that time. Thank you. Yeah, hey, Corey.

Based on the predictive nature of a reduction in proteinuria materially impacting the slope of Egfr Egfr curves at that time. Thank you.

Yeah, Hey, Corey.

Reshma Kewalramani: With regard to the 147 program, the key features of the study design are that it's a singular phase two, three study. It is a study that will enroll the broad population, so the full 100,000 patients that could be eligible for this drug. And the third feature of the study, the one you asked about, we have built in a pre-specified interim analysis at the 48-week time point. If that analysis is positive, that provides the pathway to accelerated approval. The relationship between proteinuria, that's what we studied in phase two, is a very tight, high correlation with EGFR, which is a measure of renal function.

With regard to the 147 program. The key features of the study design are that it's a singular phase two three study.

It is a study that will enroll the broad population. So the full 100000 patients that could be eligible for this drug and the third feature of this study is the one you asked about we have built in a pre specified interim analysis.

At a 48 week time point and if that analysis is positive that provides the pathway to accelerated approval.

The relationship between Proteinuria, that's what we studied in phase two is very tight high correlation with Egfr, which is a measure of renal function.

Reshma Kewalramani: And the reason I have such high confidence in the interim analysis is because the reduction in pertinuria that we saw in phase two is an unprecedented 47.6% in this very specific and very aggressive form of AMKD called FSGS. So with that 47.6% reduction in pertinuria, and you do the translations to what you would expect in terms of GFR, what I come out with is a high confidence level for the interim analysis. That was why it was so important that these three features that I mentioned were agreed upon with the agency when we went to them at the end of the phase two meeting. Very helpful. Thank you, Reshma.

And the reason I have such high confidence in the interim analysis is because the reduction in proteinuria that we saw in phase two is an unprecedented 47, 6% in this very specific and are a very aggressive form of.

A M KD called F. S. Yes, so with that 47.6% reduction in proteinuria and you do the translation to what you would expect in terms of GFR, what I come out with is a high confidence level for the interim analysis that was why it was so important that these three features that.

I mentioned them.

Were agreed upon with the agency when we went to them at the end of Phase II meeting.

Very helpful. Thank you Ashwin.

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

Reshma Kewalramani: The next question will come from Geoff Meacham with Bank of America. Please go ahead. Hi, this is Jason on behalf of Geoff.

Hi, This is Jason on for Jeff. Thanks, So much for taking our questions. Congratulations on the quarter and again want to extend our congratulations to Michael a few quick if I may could you discuss how the pain programs fit in strategically within the commercial portfolio given the focus on rare diseases.

Unknown Executive: Thanks so much for taking our questions. Congratulations on the quarter. And again, we want to extend our congratulations to Michael. A few quick questions, if I may, could you discuss how the pain programs fit in strategically within the commercial portfolio? You know, given the focus on rare diseases, basically, is this an asset you're potentially thinking about partnering with as it advances? Or are you kind of looking at maybe establishing the necessary commercial infrastructure?

Basically this is an asset you are potentially thinking about partnering with as it advances.

Are you kind of looking at maybe establishing the necessary commercial infrastructure and then it does sound like the clinical hold on <unk> was a bit of a surprise, but then again regulators have seemingly started operating with.

Reshma Kewalramani: And then, you know, it does sound like the clinical hold on A80 was a bit of a surprise. But then again, regulators have seemingly started operating with, I guess, an abundance of caution for gene and cell therapies. And do you see any potential negative read-throughs to the upcoming CTX-001 submission, or do regulators seem fairly comfortable with the safety and efficacy package as is? Thanks so much.

I guess I'm gonna buttons.

Caution for gene and cell therapies.

Do you see any potential negative read throughs to the upcoming CTX or one submission or have regulators seem fairly comfortable with that.

Safety and efficacy package houses thanks, so much.

Hey, Jason there's a few different questions in there let me try to parse it out into a pain and how we see CTX shares here one on CTX Here's your one we've been very pleased with the momentum that we've seen in this study as I said in my prepared remarks. The enrollment is complete we have dosed more than <unk>.

Reshma Kewalramani: Hey Jason, there are a few different questions in there. Let me try to parse it out into pain and how we see CTX-001. On CTX-001, we've been very pleased with the momentum that we've seen in the study. As I said in my prepared remarks, enrollment is complete.

Reshma Kewalramani: We've dosed more than 75 patients. We've secured really every regulatory designation available, prime, RMAT, orphan, here and in Europe. And we are planning forward for our filing towards the tail end of this year. On the pain program, let me make two comments, and I'm going to turn it over to Stuart to give you some more color. We see acute pain and neuropathic pain as fully vertexian. I don't feel the same way about musculoskeletal pain or something like back pain or knee pain or some other such pain that will categorize as musculoskeletal.

75 patients we've secured really every regulatory designation available prime our mat orphan here and in Europe , and we are planning forward for our filing towards the tail end of this year.

On the pain program, let me make two comments and I'm going to turn it over to Stuart to give you some more color.

We see acute pain and neuropathic pain as fully vertex Ian.

Don't feel the same way about muscular skeletal pain or something like back pain or knee pain or some some such pain that will categorize as musculoskeletal.

That being said based on the <unk>.

Reshma Kewalramani: That being said, based on Pharmacologic Validation with our own VX150 and the genetic validation, I do expect this mechanism to be effective across the three pain states. Stuart, a little more color on the commercialization. Yeah, and Jason, I think there is a bit of a misconception about us as a company that we're a rare or an orphan company. And as Reshma described, that's not how we define ourselves

Pharmacologic validation with our own VX 150.

And the genetic validation I do expect this mechanism to be effective across the three pain States Stewart, a little more color on the commercialization Yeah, and then Jason I think there is a bit of a misconception about us a company that we're a rare or an orphan company and as restaurant described that's not how we.

Stuart Arbuckle: Our research strategy is to focus on specific diseases where we understand the human biology, whether our validated targets, as Reshma said, either genetically or, in the case of NAV1.8, now pharmacologically, and they're in markets where we can access them with a specialty infrastructure. And we think pain fits that description perfectly. As Reshma said, there are various different segments of the pain market that you can think about, such as acute, neuropathic, and chronic musculoskeletal.

Been ourselves our research strategy is to focus on specific diseases, where we understand the human biology, whether all valid target validated targets as restaurants said either genetically or in the case of our NAV one eight now pharmacologically.

And they are in markets, where we can access them with a specialty infrastructure and we think pain fits that description perfectly as restaurants had this various different segments of the pain market that you can think about acute Europe pathic in the chronic kind of musculoskeletal the commercial opportunity in the acute pain segment is enormous.

Stuart Arbuckle: The commercial opportunity in the acute pain segment is enormous. Acute pain accounts for over 1.5 billion treatment days a year in the U.S. alone. And despite more than 90% of those prescriptions being generic, the market is valued at $4 billion.

Acute pain accounts for over 1.5 billion with a b treatment days a year in the U S alone and despite more than 90% of those prescriptions being generic the market is valued at $4 billion.

Stuart Arbuckle: So if we are able to bring forward an asset that has opioids or better efficacy without the side effect liability of opioids and other pain medications, we think the opportunity is very, very significant in acute pain, a multi-billion dollar opportunity in acute pain. And as Reshma said, similarly in neuropathic pain, a multi-billion dollar opportunity, that's also a specialty market that we could service through a specialty Perfect. Thanks for the color.

So if we are able to bring forward an asset that has opioid or better efficacy without the side effect liability of opioids and other pain medications. We think the opportunity is very very significant and acute pain multibillion dollar in acute pain opportunity and as regimen said similarly in neuropathy pain multibillion dollar.

Attunity, that's also a specialty market that we could service through a specialty infrastructure.

Perfect. Thanks for the color.

The next question will come from Robin Karnofsky guests with Truest Securities. Please go ahead.

Unknown Executive: The next question will come from Robyn Karnauskas with Truist Securities. Please go ahead. Hi, thank you so much. And Michael, I'm sad to see you go.

Unknown Executive: But congratulations on all the hard work you put in at Vertex. So, two quick ones on the inclusion criteria for your phase three trial for AMKD. How challenging do you think the enrollment might be?

Hi, Thank you so much and Michael and Sad to see you go but congratulations on all the hard work you put in at vertex. So extra few quick one since the equipment from the inclusion criteria for your phase III trial for an Katy.

How challenging do you think the enrollment might be and you've indicated there was a 100000 patients.

How many are actually genotype are seeking treatment you have to do more work to actually get them genotype and.

Reshma Kewalramani: You know, you've indicated there are 100,000 patients. How many are actually genotypes seeking treatment? Do you have to do more work to actually get them genotypes?

Second question is really on them.

C check there is there one could.

Reshma Kewalramani: And, second question is really on CTX001. Could you just give us some more color as you've been talking to more of the centers, maybe buckets of patients that would be the initial patients most likely to go on this drug and what their characteristics are? And are you creating a registry or a list of patients who might be willing to start therapy? Thanks. I'm going to start with AMKD, and then I'll ask Stuart to provide some color on the patients with both sickle cell disease and beta thalassemia for the CTx001 program.

So just given some more color as you've been talking tomorrow. The center, maybe buckets of patients that would be the initial patient.

Patients most likely to find drug and what their characteristics are and are you, creating a a registry or a list of patients who might be willing to start therapy.

Sure I'm going to start.

On a M. Katy and then I'll ask Stuart to provide some color on the patients for both sickle cell disease and beta thalassemia for the CTX Here's your one program.

Reshma Kewalramani: Robyn, the key criteria for entry into the AMKD study are proteinuria, reduced renal function, and two ApoL1 alleles by genotyping. The actual genotyping test is fairly simple. It's a simple blood test, but you are right that it is not commonly performed.

The key criteria for entry into the a M. KD study is curtained Orient.

Reduced renal function and to April one <unk> by Genotyping.

The actual Genotyping test is fairly simple, it's a simple blood test, but you are right that it is not commonly performed and the reason it's not commonly performed is because before now we didnt really have anything to offer our patients who had April one mediated kidney disease.

Reshma Kewalramani: And the reason it's not commonly performed is because, before now, we didn't really have anything to offer our patients who had ApoL1-mediated kidney disease. Recognizing that, we've added some features to our phase two, three clinical trial to ensure that we will have the kind of enrollment that we seek and that we can bring this medicine forward with speed. The first is that it's a global study with many sites up and running in the US and in the EU.

Recognizing that we've added some features into our phase two three clinical trial to ensure that we will have the kind of enrollment that we seek and that we can bring this medicine forward with speed. The first is it's a global study with many sites up and running in the U S and in the E.

You bet.

Reshma Kewalramani: The second is that all patients are on standard of care, so there is no patient who is going to have to go onto placebo to be part of the study. This is a study where one arm gets standard of care plus VX147, and the other arm gets standard of care.

The second is all patients are on standard of care. So there is no patient he was going to have to go on to placebo to be part of the study. This is a study where one arm get standard of care plus VX 147, and the other arm get standard of care and third we ever concurrent.

Stuart Arbuckle: And third, we have a concurrent genotyping study up and running where patients can get genotyped, and they can, if they wish, then enroll in the phase two, three study. I think that those measures are going to be very helpful as we make progress on enrollment. Stuart, I'm going to turn it over to you for CTx001 and patients that you. Yeah, Robyn, thanks for the question. So, as we've commented previously, there are about 150,000 patients who have sickle cell disease or transfusion-dependent Thalassemia in the US and the EU.

Typing study up and running where patients can get genotype and they can if they wish then enroll in the phase two three study I think that those measures are going to be very helpful. As we make progress on the enrollment Stuart I'm going to turn it over to you for CTX, Here's your one and patients.

That you see yeah Robyn thanks for the question. So as we've commented previously there's about 150000 patients who have sickle cell disease or transfusion development.

Stuart Arbuckle: However, as you can imagine, we don't think that that is the entire population who's gonna be eligible for CTX001 given the current conditioning regimen. So based on the inclusion criteria in our study, but also our research and other people's research, talking to physicians about the types of patients that they think are likely to be potential candidates, we think that's around 32,000 of the 150,000. Of those 32,000, about 25,000 of those are sickle cell, the majority of which are here in the US.

Hence fusion dependent thalassemia.

In the U S and the EU.

As you can imagine we don't think that they're all that that is the entire population is going to be eligible for CTX, Arizona won't given the current conditioning regimen.

So based on the inclusion criteria with our study, but also our research and other People's research our.

Talking to physicians about the types of patients that they think are likely to be potential candidates.

Think that's around 32000 of the 150000 of that 32000 and about 25000 to those off sickle cell.

The majority of which are here and you in the U S. So that is the patients that we think are likely be potential candidates for CTX are zero, along with the existing view south on base conditioning regimen.

Stuart Arbuckle: So those are the patients that we think are likely to be potential candidates for CTX001 with the existing BuSAL fund-based conditioning regimen. Thank you. The next question will come from Salveen Richter with Goldman Sachs. Please go ahead.

Thank you.

The next question will come from Celgene richer with Goldman Sachs. Please go ahead.

Unknown Executive: Thank you for taking my questions. And Michael, it has been a pleasure working with you. You'll be very missed here.

Thank you for taking my question and Michael It has been a pleasure working with you you'll be very missed here.

Hum.

Two clinical questions one on C check series there one on the commercial front, how much precedent has been set on the payer front globally by Bluebird, particularly given their difficulty with the EU and then secondly on the Duchesne gene editing program could you just provide some details on the construct.

Unknown Executive: Two clinical questions. One, on CTX001. On the commercial front, how much precedent has been set on the payer front globally by Bluebird, particularly given their difficulty with the EU? And then secondly, on the Duchenne gene editing program, could you just provide some details on the construct? And is this in partnership with CRISPR? Thank you. Salveen, I'm going to start with the DMV question, and then I'm going to turn it over to Stuart to talk about CTX. The DMD program is one I know, Salveen, you've asked me about before. In just one second, I'm gonna turn it over to Bastiano.

Is this in partnership with CRISPR.

Thank you.

So I mean I'm going to start with the D. M. D question, and then I'm going to turn it over to Stuart to.

Talk through CTX.

The DMD program is one I noticed I mean, you've asked me about before and just one second I'm going to turn it over to Bastian out we've made really nice progress on that program. This is a gene editing based program and we are in our IND, enabling studies with the <unk> plan.

Reshma Kewalramani: We have made really nice progress on that program. This is a gene-editing-based program, and we are in IND-enabling studies with the IND plan for next year. Bastiano, can I ask you to give a little bit more color on this?

For next year, but as you know can I ask you to give a little bit more color on this sure.

So our approach to.

Bastian Osana: Sure. So our approach to... D&D is a little bit different than all the other gene therapy approaches. Because we have deliberately actually chosen to go with like a near full length exon skipping dystrophin approach which is based on human genetics because as you know patients with Backer dystrophy for example have a near full length dystrophin and therefore they are very mildly, The gene therapy approaches that are used in other contexts, they only deliver a truncated version of the dystrophin of various lengths, but it's called microdystrophin for a reason.

DMD is a little bit different than all the other gene therapy approaches.

Because we have deliberately actually chosen to go.

With that like a near full length.

Exco exon skipping dystrophin approach.

Which is based on human genetics, because as you know patients with Becker.

Dystrophy for example, it ever near full length dystrophin, and therefore, the very mild disease.

The gene therapy approaches that are used by by you know in in other in other contexts. They only delivered a truncated version of the dystrophin of various lengths, but the it's called micro dystrophin for a reason gene editing is actually all the approach that has the potential to deliver the near full length proteins.

Bastian Osana: Gene editing is actually the only approach that has the potential to deliver the near full-length protein, which is required for what is believed to be a durable, transformational, and functional cure. You'll remember that this program came to us through the acquisition of Exonix. And since then, we have worked really, really hard on both analytical and process development for our technology. Because given what has happened in the field, we really paid close attention to purity and all the things like analytical development and process development to be sure that we have the best product technology as opposed to together with science.

<unk>, which is.

Higher for what they believe is going to be a durable transformational.

Functional cure you.

Remember that.

This program came to us through the acquisition of <unk> and since then we have worked really really hard on both analytical and process development for our technology, because given you know what.

As offered in the field that we really paid close attention to those purity and all the things like co development and process development to be sure that we have the best product.

Technology.

July is as opposed to us together with our science. So we feel very optimistic about our approach in.

Bastian Osana: So we feel very optimistic about our approach and, as Reshma said, very pleased to be in IND enabling studies. And we aim to file the IND in 2023 and begin clinical development soon thereafter. Yeah, and Salveen on transformative therapies and, you know, payment models, which I think was the basis of your question. You know, I don't think what happened with Bluebird has set a precedent that transformative one-time functional cures are never going to get paid for in the EU or elsewhere.

Swisher said very pleased to be in IND, enabling studies and we aim to file the NDA in the middle and in the into this industry.

And begin clinical development soon thereafter.

Yeah, and shelving on on transformative therapies and.

Payment models, which I think was the basis of your question you know I don't think what's happened with with Bluebird has set a precedent that transformative onetime functional cures are never going to get paid for.

In the EU or elsewhere.

Bastian Osana: Clearly, there's disappointment in the community about the license withdrawal, but we, as part of our pre-launch planning, are engaging with payers both here in the U.S. and overseas, and based on the capabilities that our team has demonstrated in securing reimbursement for CF given the transformative potential that CTX001 holds, I'm optimistic that we will be able to bring that medicine to patients around the world pending license approval. Operator, we're ready for the next question. The next question will come from Michael Yee with Jeffries. Please go ahead.

Clearly there's disappointment in the community about the license withdrawal. However, we as part of our prelaunch planning are engaging with payers both here in the U S and overseas.

Based on the capabilities that our team has demonstrated in securing reimbursement for C. F. Given the transformative potential. The CTX 001 holds I'm optimistic that we can be able to bring that medicine to patients around the world.

Pending license approval.

Okay.

Operator, we're ready for the next question.

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

Yeah.

Unknown Executive: Thanks for the question and thanks to Mike, thanks to Mike as well. We really appreciate it. Um, we had two questions on ApoL1 mediated kidney disease.

Thanks for the question and thanks to Mike Thanks to Mike as well, we really appreciate it.

We had two questions on <unk> on April one mediated kidney disease and the first question was just around your confidence in enrolling the phase II portion and whether or not you expect that data at the end of the year and what you can say about that so going back to follow up in terms of identifying these patients.

Unknown Executive: The first question was just around your confidence in enrolling the phase two portion of the study and whether or not you expect to have data at the end of the year and what you can say about that. So it goes back to sort of follow-up in terms of identifying these patients and speeding up the confidence of getting these people enrolled. And the second question relates to the phase three portion, which is on EGFR, and whether or not you have a good idea about the slope of decline over a time period for these patients and whether or not there's any heterogeneity between the different diseases within AMKB and what you're assuming in the phase three on decline. Thank you. Yeah,

Speed and confidence of getting these people enrolled and the second question relates to the phase three portion, which is an egfr <unk> and whether or not you have a good idea around the slope of decline over a time period for these patients and whether or not theres any heterogeneity between the different diseases within a M D.

What you're assuming for in the phase III on decline. Thank you.

Yeah.

Reshma Kewalramani: Mike, with regard to enrollment, it is really simply too early to comment on enrollment dynamics for VX147. We presented and shared the Phase 2 data just in December, and Phase 3 started just three months after that in March. So, a little too early to call, but as I commented, I think the genotyping study, the number of trial sites that we are opening around the globe, and the fact that this is a study where both arms get treatment will help with enrollment.

Mike.

With regard to enrollment it is really simply too early to comment on enrollment dynamics for VX 147, we presented and shared the phase II data just in December in the phase III start at just three months after that in in March So a little too early to call, but as I commented.

I think the Genotyping study the number of trial sites that we are opening around the globe and the fact that this is a study where both arms get treatment will help with enrollment.

Reshma Kewalramani: On the GFR question in the Phase 3 portion, this group of patients, those with two April one alleles, have a very rapid decline. And when I say that, I mean, north of five cc per year.

The GFR question in phase the in the phase three portion.

The this group of patients those with two April one allele have.

A very rapid decline and when I say that I mean, north of five <unk> per year.

Reshma Kewalramani: And when you have that kind of rapid decline, it gives you the opportunity to assess the impact of your drug, which is why this one-year accelerated endpoint potential is really important. So what we demonstrated in phase two is a reduction in pertinuria. That was an approximately 50 percent reduction, 47.6. That is very tightly correlated with the EGFR, the measure of kidney function, and the measure of kidney function in people with two APOL1 alleles, regardless of whether you call it FSGS or you call it another disease, is very high.

And when you have that kind of rapid decline. It gives you the opportunity to assess the impact of your drug which is why this one year.

Celebrated endpoint potential is really important so what we demonstrated in phase two is reduction in proteinuria that was the approximately 50% reduction 47.6 that is very tightly correlated with the egfr the measure of kidney function and the measure.

A kidney function in people with two April one o'neill's, regardless of whether you call. It F S GFS or you call. It another disease is very high so I feel very good about where we are in terms of getting the clinical trial up and running and very good about the way we designed the endpoint on boats.

Reshma Kewalramani: So I feel very good about where we are in terms of getting the clinical trial up and running and very good about the way we've designed the endpoints for both pertinuria and EGFR. Okay, thanks. The next question will come from Phil Nadeau with Cowan and Company. Please go ahead. Good afternoon, Michael.

Maryann Egfr.

Okay. Thanks.

The next question will come from Phil Nadeau with Cowen <unk> Company. Please go ahead.

Unknown Executive: Let me add my thanks for all your help over the years. Best of luck in your next adventures. You're certainly going to be missed here.

Unknown Executive: Two questions from us. First, a brief commercial and then VXA 80. On the commercial, last quarter you called out inventory build. You haven't mentioned inventory yet on the call, so I'm curious where inventory stands and where there is the stocking in the quarter. And second, on VXA 80, appreciating it's still early days since the clinical hold was initiated, but do you have any sense of why the FDA is not convinced? I think in the press release you mentioned they didn't believe the benefit risk was positive. Is that because they don't think you need more benefits, or is there some risk they're worried about?

Reshma Kewalramani: And then, second on VXA 80, you have one ex-US trial site. Any desire to increase the numbers to continue enrolling patients while the US hold is instituted? And last, of course, if you have any...

Reshma Kewalramani: Preliminary thoughts on what you'll need to do to release the hold, we'd all be curious to hear. Thanks. Let me ask Charlie to start with your question on inventory for the quarter. Charlie, do you want to talk a little bit about revenues for the quarter and how you see inventory? Yes.

Charlie Wagner: Thanks for the question. As we've mentioned previously, it's not at all uncommon for us to see channel inventory and patient inventory fluctuations quarter to quarter on the order of magnitude of $20 to $50 million. We called out an inventory increase in the fourth quarter. We did see some destocking in the first quarter, just didn't call it out specifically.

Common for us to see channel inventory and patient inventory fluctuations quarter to quarter on the order of magnitude of $20 million to $50 million, we called out an inventory increase in the fourth quarter. We did see some destocking in the first quarter just didn't call it out specifically.

Reshma Kewalramani: And with regard to your questions on VX880, Phil, what we shared earlier this week is what we know. By regulation, the agency has 30 days to provide us with its list of questions or its information requests. We are highly confident in this program and deeply committed to type 1 diabetes, and we're looking forward to constructively and expeditiously working with the agency to resume the trial in the U.S. as soon as possible. The trial is up and running, as you rightfully point out, in two regions right now, in the U.S. and in Canada. The trial remains up and running in Canada.

And with regard to your questions on V X 880 fell what we shared earlier. This week is what we know by regulation. The agency has 30 days to provide us their list of questions or their information request.

We are highly confident in this program and deeply committed to type one diabetes and we're looking forward to constructively and expeditiously working with the agency to resume the trial in the U S. As soon as possible.

The trial is up and running as you rightfully point out in two regions right now in the U S and Canada. The trial remains up and running in Canada. We have not received any word from health, Canada for any questions or concerns that they have.

And with regard to opening up additional sites that's always been in the plan. It has nothing to do with the the hold in the U S and we intend to have more sites coming on.

In time.

That's very helpful. Thank you.

Reshma Kewalramani: We have not received any word from Health Canada on any questions or concerns that they have. And with regard to opening up additional sites, that's always been in the plan. It has nothing to do with the hold in the U.S., and we intend to have more sites coming on in time. That's very helpful. Thank you. The next question will come from Klein Bristow of UBS, please go ahead. Hey, thanks. This is Colin.

The next question will come from Klein Bristow with UBS. Please go ahead.

Unknown Executive: Good afternoon. Congratulations on the quarter, Michael. Thank you for the help and all the best in the future. First of all, Reshma, we had previously spoken before the AbbVie readout, and you talked about the amount of contemplative intelligence work you had done. And this ultimately gave you confidence that the AbbVie triplet would not be a threat. Clearly, this was on point.

Hey, Thanks, This this call and.

Good afternoon, congrats on local to Michael Thank equal to help and all the best in the future <unk>. We had previously spoken before the abbey read out and you talked about the amount of competitive intelligence. What he had done and this ultimately gave you confidence that that'd be trip that would not be a threat to any of this was.

Reshma Kewalramani: I'm curious if you have any early thoughts or insights into the next-gen PG corrector. I think it's AbbVie 576 that they plan to advance into the clinic. And then also on the competition side, there was some press recently about Siona Therapeutics, which has assets targeting the NBD1 domain. So I'd be curious to get your take on this approach also.

<unk> I'm curious if you had any thoughts so in thought and cause the next and please do correct I think it's at the 576 that they plan to advanced into the clinic and then also on the competition sorry. There was some press recently about C O and the therapeutics, which have assets talk to the in N. B D. One domain, so it'd be cute.

To get your take on this approach all set thanks.

Unknown Executive: Thanks. Yeah, hey, Colin. I'll start, and I'm going to ask David to add a little comment. Colin, I won't speak directly to any competitor, you know; that's not my practice, but let's talk about CF in general. Over the years, we've established a leadership position in CF, and we've not only sustained it, but we've expanded it. And our goal of out-innovating ourselves, and if possible, even bringing more efficacious medicines forward than Trikafta, and absolutely, in the case of the last 5,000 patients, bringing forward a nucleic acid therapy for them that remains unchanged. Trikafta is the standard of care today, and the closest competitor to Trikafta has been and remains today our own VX121561 tezaca

Yeah, he called them, all started and I'm Gonna ask David too to add a little comment.

Uhm.

Colin I won't speak directly to any competitor a you know that's not my practice, but let's talk about C. F in general.

Over the years, we've established a leadership position in C F and we've not only sustained it but we've expanded it.

And our goal of out innovating ourselves and if possible, even bringing more efficacious medicines forward, then try casta and absolutely in the case of the last 5000 patients, bringing forward of nucleic acid therapy for them that remains unchanged.

Try character.

Is the standard of care today.

And the closest competitor <unk> casta.

Has been and remains today are owned the X 121561, Keswick after I'm Gonna ask David to just give you a few comments on why we have so much confidence in our molecules in the H B E essays, which are really the workforce and the translational element of of what we do David.

Reshma Kewalramani: I'm gonna ask David to just give you a few comments on why we have so much confidence in our molecules and the HPE assays, which are really the workhorse and the translational element of what we do. David, a few comments on our confidence and why we know when we have something in the lab, it translates into the clinic. Absolutely, Reshma.

Comments from you on our confidence and why we know when we have something in the lab it translates into the clinic absolutely <unk> as.

David Altshuler: As you've seen over the years, the Vertex deployment of the HPE assay has proven itself over and over again to be translationally relevant and predict clinical outcomes. And that's been true through Glydeco, Orkambi, Symdeco, VX445, Trikafta, and also with VX121, that triple, where we saw improved chloride transport in the HPE assay. We also, as you remember, did a phase two study that showed improved sweat chloride and other very promising attributes, such as the FEV1 change. So we really believe in that assay, and we've proven it out. We do continue to work on small molecules to outdo not just Trikafta but VX121, which is in phase three.

You've seen over the years the vertex deployment of the H B E. S has proven itself over and over again to be translational irrelevant and predict clinical outcomes and that's been true through <unk> <unk> five for a cabinet and also with the X one to one that triple where we.

Saw it improved Florida transport and the H B E. S. A we also as you remember did a phase two study that showed improved sweat chloride and other a very promising afternoon, such as the F. B one change. So we really believe in that essay we've proven it out we do continue to work on small molecules to outdo.

Not just tried cast them, but the X 121, which is in phase three and we do follow everything that goes on and we believe that the most promising molecules that could possibly challenge of the XOR for five or 1121, triple and those things we might bring beyond it.

David Altshuler: And we do follow everything that goes on, and we believe that the most promising molecules that could possibly challenge VX445 are our own 121 triple, and those things we might bring. Thank you. The next question will come from Mohit Bansal with Wells Fargo. Please go ahead.

Thank you.

The next question will come from <unk> with Wells Fargo. Please go ahead.

Unknown Executive: Great, thanks for taking my question. And again, my congratulations and thank you very much for Michael as well. So maybe a couple of questions on the diabetes program. Could you comment on the C-peptide levels for the first patient at days 270? Was there an increase after day 150? And when do you expect to see a plateau, a plateauing effect, for C-peptide?

Great. Thanks for taking my question and again my congratulations and thank you very much for Michael as well.

So maybe a question a couple of questions on on on the diabetes program could you comment on the C peptide levels for the first patient that these 270 was there an increase after D 150, and do you when do you expect to see a plateau effect for C-peptide.

Reshma Kewalramani: And last one related to that, do you have a target C-peptide level for these patients that might lead to insulin independence eventually? Thank you. Yeah, Mohit, really good questions. I'm going to reframe the question a little bit and ask Bastiana to comment, but I want to make sure I explain this well. The way you know that a patient is insulin independent is actually by a very strict criteria. And that strict criteria is that they don't take insulin any longer, exogenous insulin. Their fasting glucose level is less than 126, and their postprandial, that is to say, after food, glucose level is less than 180.

And last unrelated is that did you have a target C peptide level for these patients that might lead to insulin independence. Eventually thank you.

Yeah, well, that's really good questions I'm Gonna Reframe the question, a little bit and ask Buffy ended a comment but I want to make make sure I explain this well the the way you know that a patient is insulin independent.

Actually is by a very strict criteria and that strict criteria is they don't take insulin any longer exogenously insulin.

Their fasting glucose level is less than 126.

And their post prandial, that's to say after food glucose level is less than 180, and the reason we're able to declare patient number one as insulin independent is because they meet all of those criteria now.

Bastian Osana: And the reason we're able to declare patient number one as insulin-independent is because they meet all of those criteria. Now, you ask a good question about what we expect in terms of durability of effect. And I'm going to turn it over to Bastiano to talk about the experience with catavaric transplants, the quantity and quality of our cells, and why we think that our approach is a durable, long-term, durable approach.

Now you ask a good question about what do we expect in terms of durability of effect and I'm Gonna turn it over to Bastian Ah to talk about the experience with cat Varick transplants, the quantity and quality of ourselves and why we think that our approach is a durable longterm durable approach by Sienna.

Bastian Osana: Thanks, Reshma, and it actually allows me to talk about what is really important in this program, which is the quality and the nature of our cells. So our cells are fully differentiated, indistinguishable from naturally occurring beta cells, so they share a common biology. Now, what we know about the biology of beta cells is that at birth, they're pretty much all set when it comes to their numbers and their differentiation, which means that they last a lifetime.

Thanks for asthma and <unk>.

He actually allows me to talk about what is it important in in his prime with choose the quality in the nature of out of ourselves. So ourselves are fully differentiated undistinguishable thrall naturally a cooler and better so so they share a common.

<unk> no what we know about the biology of beta cells is that at birth, the pretty much all set when it comes to the numbers and the the the differentiation, which means that they lost a lifestyle that is what is known about this of that is actually.

Bastian Osana: That is what is known about the cells. That is actually consistent with what has been learned over the years with cadaveric islets, where when patients are compliant with immunosuppressive therapy and the transplant is therefore successful, these cells can last for a very, very long time. So our cells, we believe that being of the same biology and in the context of a similar therapeutic approach, being an islet transplant, we believe that there is the potential for the cells to last as long as the natural beta cells do, which is a lifetime. When it comes to The... I think that was a question. Yeah. Thank you. Sure thing. The next question will come from Evan Seigerman with BMO Capital Markets. Please go ahead.

Consistent with water S being learn over the years with Covid eyelets, where when the patients are compliant with immuno suppressive therapy and the telephone is therefore successful. These cells can last for a very very long time.

So ourselves, we believe that being of the same biology and in the context of a similar therapeutic approach being a tourist month, we believe that it has the potential for the sauce to last as long as the natural beta cells, which is a lifetime.

When it comes to the.

I think that was I think that was.

Yeah.

Thank you.

Sure thing.

The next question will come from Evans Tigerman with BMO capital markets. Please go ahead.

Unknown Executive: Hi, all. Thank you so much for taking my question. And I'll just add, Michael, thank you for everything over the years. You will be missed greatly. Charlie, one for you.

Hi, all thank you so much for taking my question and I'll put that Michael. Thank you for everything over the years you will be missed greatly Charlie one for you I love. It if you could speak to the impact of F. Excellent Oh, you ourselves I don't think you mentioned anything in your prepared remarks, and does that factor into your decision doctorate guidance, despite expanded reimbursement pointing to kind of what you announced.

Australia recently.

Charlie Wagner: I'd love it if you could speak to the impact of FX on OUS sales, but I don't think you mentioned anything in your prepared remarks. Did that factor into your decision not to raise guidance despite expanded reimbursement? I'm pointing to kind of what you announced in Australia. Yeah, Evan, thanks for the question. Again, just to remind folks, the reiterated guidance for revenue of 8.4 to 8.6 billion sets us up for another really strong year, that's a billion dollars above 2021 and 12% growth.

Yeah, even thanks for the question again, just to remind folks the the reiterated guidance for revenue 8.4 to 8.6 billion sets us up for another really strong year, that's a billion dollars above 2021, and 12% growth as we reiterated the guidance. We considered a number of puts and takes US trillions of course is is good news.

That we've had this year, we also considered things like inventory fluctuations in F X, which is very modest headwind all of that taken together, we feel as accurately captured in the 200 million dollar range between the low and and the high end of guidance.

Charlie Wagner: As we reiterated the guidance, we considered a number of puts and takes. Australia, of course, is good news that we've had this year. We also considered things like inventory fluctuations and FX, which is a very modest headwind.

Excellent and then no real impact on effects are kind of can you speak more to that.

Charlie Wagner: All of that taken together, we feel is accurately captured in the $200 million range between the low end and the high end of guidance. Excellent. And then, no real impact on FX or kind of, can you speak more to that? Yeah, it's pretty modest, you know, two-thirds of our revenues are in the US, one-third outside the US. We have a very active and very effective hedging program that blunts some of the impact of foreign exchange changes. And so for us, the impact with, again, sort of, a baseline 12% growth rate, the relative impact of FX is pretty modest and very small compared to some of our peers.

Yeah, It's it's pretty modest you know two thirds of our revenues are in the U S. One third X U S. We have a very active and very effective hedging program that blunt some of the impact of foreign exchange changes and so for us the impact with again with sort of a baseline 12% growth rate the relative impact of ethics is it.

Is pretty modest and very small compared to some of our peers.

Charlie Wagner: Excellent. Thank you for that call. I appreciate it. Operator, we have time for one more question. The next question will come from Liisa Bayko with Evercore ISI. Please go ahead. I guess we'll be the last one to thank Michael for all of his hard work, and we'll hope you'll keep in touch with us. You bet.

Excellent. Thank you for that color I appreciate it.

Operator, we have time for one more question.

The next question will come from Lisa <unk> with Evercore ISI. Please go ahead.

I guess it will be the last one to to thank Michael for.

For all of his hard work and I hope, you'll keep in touch with.

<unk>.

You bet. Thanks.

Unknown Executive: Thanks. I just want to see if we can get a little more detail on some of the type 1 diabetes metrics. Like, for example, we don't have some of the, you know, HBA1C numbers for patient 2 at day 90, and it would just be nice to see how that's tracking. I know there was a reduced exogenous insulin use, so that's good. And then some of the other things, I guess. Are you saying that if you didn't mention the C-peptide, maybe it hadn't reached an appropriate level yet? I'm just curious because the peak simulated wasn't, wasn't shown either for some of those endpoints, those, those time points. So just curious to fill in some of the holes.

I just wanted to see if we get a little more detail on some of the type one diabetes matrix like for example, we don't have some of the you know H B a one C number for patient 280 90.

And it would just be nice to see how how that's tracking I know there was a <unk> <unk>. So that's good and then some of the other I guess if you are you, saying that you didn't mention that the M. C peptide maybe it hadn't reached an appropriate level, yet I'm, just curious because of peaks and you're right. It wasn't.

<unk> shown either for some of those and those that those time points just curious to fill in some of the holes here.

Reshma Kewalramani: Yeah, sure thing. Lisa, we shared a fair amount of data on all three patients' doses to date, the first two patients at half dose and the first full dose patient who is at the day 30 milestone. Across all of the patients, in terms of efficacy, we see really good efficacy. And we've shared it out to day 270 on patient number one, who is insulin independent. You're right; we haven't shared all of the details at all of the time points across the patients.

Yeah sure thing Lisa we shared a fair amount of data on all three patients dose to date. The first two patients had half dose and the first full dose patients who is at the day 30 milestone.

Across all of the patients in terms of efficacy, we see really good efficacy and we've shared now out today to 70 and patient number one who is insulin independent you're right. We haven't shared all of the details at all of the time points across the patients, but you should expect us to share.

Reshma Kewalramani: But you should expect us to share all of the details in terms of hemoglobin A1C, C-peptide levels, stimulated and fasting, as well as the CGM, that's the continuous glucose monitoring data. And, of course, all safety at upcoming Congresses this year. So you will see all of the data on the patients with all of the follow-up. Okay, great.

All of the details in terms of hemoglobin, a one C C peptide levels stimulated and fasting as well as the C. G M. That's the continuous glucose monitoring data.

And of course, all safety at upcoming Congresses. This year. So you will see all of the data on the patients with all of the follow up.

Reshma Kewalramani: And then just one more question, if I may. Sorry, I might have missed this earlier, but for CTX-001, have you finalized what you need to file with FDA? And then if you could give us an indication of where you're going to present the data in the next data update, that would be great. Thank you. Yeah, on CTX-001, we shared last data on, I believe, 22 patients last year at the European hematology meeting. We have now dosed over 75 patients, so we have substantially more information.

Okay, Great and then just one more question if I may.

Sorry, I might've missed this earlier, but first he kicked O. One have you finalize what you need to file with F. D. A and then if you could give us an indication of where you're gonna present. The data. The next day to update that'd be great. Thank you.

Yeah on CTX fears your one we shared last data on I believe 22 patients last year at the European Hematology meeting, we now have dosed over 75 patients. So we have substantially more information and you should expect to see that.

Reshma Kewalramani: And you should expect to see that at upcoming Congresses this year. With regard to the data package for the agency, what we need to do, as we've discussed, is complete our discussions with them. And the two outstanding areas of discussion are the number of patients and the duration of follow-up that they would like to see in the filing. You know, we have all of the designations like RMAT and ORFIN and such, so we've had the opportunity to have conversations that have brought us to this point.

At at upcoming Congress is this year.

With regard to the data package for the agency, what what we need to do as we've discussed is complete our discussions with them and the two outstanding areas of discussion or the number of patients and the duration of follow up that they would like to see in the filing you know we <unk>.

Have all of the designation like arm add an orphan and such so we've had the opportunity to have conversations that bring us to this point, it's now wrapping up those conversations with both the U S and the EU to wrap up on the discussion of numbers in duration.

Reshma Kewalramani: It is now wrapping up those conversations with both the U.S. and the EU to wrap up the discussion of numbers and duration. Right, and it seems like you've done a bunch of work on, you know, sort of the market, and it looks like the market's relatively concentrated. Do you have any sense of sort of capacity and how we should think about, you know, how many patients could be treated in the current scenario on a yearly basis? Yeah, Liisa, I think you're asking about in the US and EU. How do we see bed capacity for patients to be able to come in and have the procedure for CTx301?

Right now it seems like you've done a bunch of work on you know sort of the market and it looks like the market's relatively concentrated.

Do you have any sense of sort of capacity and how we should think about you know how many patients can be treated in the current scenario.

Really basis.

Reshma Kewalramani: And since we're out of time, I'll just take it really quickly. Stuart and the team have mapped this out. It is very concentrated.

Yeah at least I think you were asking about in the U S. N E U how do we see bed capacity for patients to be able to come in and have the procedure for CTX spheres erewhon and since we're out of time I'll just take it really quickly Stewart and the team have a map. This out it is very concentrated the overwhelming majority of patients and.

You you qualify for this therapy are concentrated in four countries. The overwhelming majority of patients in the U S who qualify for this therapy are concentrated in less than 25 states and we have mapped out the centres, where they would be treated and yes, we see that the numbers of patients that we expect to be.

Reshma Kewalramani: The overwhelming majority of patients in the EU who qualify for this therapy are concentrated in four countries. Similarly, the overwhelming majority of patients in the US who qualify for this therapy are concentrated in less than a third of the countries in the EU. And we have mapped out the centers where they would be treated. And yes, we see that the numbers of patients that we expect to be treated are going to have a way to be done in centers with the right expertise. Thank you very much. This concludes our question and answer session. I would like to turn the conference back over to Mr. Michael Partridge for any closing remarks. Please go ahead.

[noise] treated them are going to have a way to have that done in centers with the right expertise.

Thank you very much.

This concludes our question and answer session I would like to turn the conference back over to Mister Michael Partridge for any closing remarks. Please go ahead.

Michael Partridge: Thanks, operator. Thanks, everybody, for joining the call tonight. Thank you also for all of your kind words. They are very much appreciated. It has been an honor and a privilege to represent Vertex, and it's also been fun to interact with all of you. As always, the team and I are in the office tonight. If you have additional questions, take care, and have a good evening. The conference is now concluded. Thank you for attending today's presentation. You may now disconnect. Unknown Executive, Unknown Attendee, Unknown Attendee, Unknown Attendee, [inaudible] BF-WATCH TV 2021 Buy Zoom to sell your own products, [inaudible] BF-WATCH TV 2021

Thanks, operator, thanks, everybody for joining the call Tonight. Thank you also for all of your kind words very much appreciated. It has been an honor and a privilege to represent vertex and it's also been fun to always interact with all of you is.

As always the team and I are in the office Tonight. If you have additional questions take care and have a good evening.

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

Mmm.

[music].