Vertex Pharmaceuticals Incorporated

Good afternoon and welcome to the Vertex Pharmaceuticals second quarter 2023 earnings conference call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star, then two. Please note, this event is being recorded. I would now like to turn the conference over to Suzy Lisa, Senior Vice President, Investor Relations. Please go ahead.

Good evening, everyone. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our second quarter 2023 Financial Results Conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Operating Officer, and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation those regarding Vertex's marketed cystic fibrosis medicines, our pipeline, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. In addition, the impact of foreign exchange is presented inclusive of our foreign exchange risk management program. I'll now turn the call over to Reshma.

Thanks Susie. Good evening all and thank you for joining us on the call today. After a strong start to the year, we saw continued momentum into the second quarter across all aspects of the company. Our CF business continues to grow and we are reaching more patients than ever. In the second quarter, this expanded reach drove 14% global CF product revenue growth versus the prior year period. And with this first half performance, we are raising our full year 2023 CF product revenue guidance to a revised range of $9.7 to $9.8 billion. As we continue to deliver in CF, we're also investing for future commercial excellence ahead of multiple potential near-term launches. In excess cell in both severe sickle cell disease and transfusion-dependent beta thalassemia, which we expect will be the first in our next wave of launches. In VX548 for acute pain, another multi-billion dollar commercial opportunity. And in our Vanzecafta triple combination therapy for cystic fibrosis, which provides the opportunity to further extend our leadership in CF. In addition to these four disease areas, our mid-stage clinical pipeline continues to develop rapidly and mark progress towards our five launches in five years' goal. Recent achievements include the VX147 or Anaxiplin pivotal trial remains on track to complete the Phase IIb portion of the study by the end of this year. in our Type 1 diabetes program. Both VX880, the naked cells, and VX264, the cells plus device programs, are now in the clinic and dosing patients. Additionally, we announced a strategic long-term manufacturing agreement with Lonza for our Type 1 diabetes cell therapy programs. And finally, an accelerated timeline for the VX548 Phase 2 study in peripheral neuropathic pain, where we now expect the study to complete by the end of 2023. In total, we're advancing programs in eight disease areas through mid- and late-stage development, six of which are now past the proof-of-concept stage, as detailed on slide 5. Beyond our clinical pipeline, we're also advancing the next wave of research stage assets, reflecting programs sourced from both internal and external innovation. This includes programs in Duchenne's muscular dystrophy, myotonic dystrophy type 1, the NAV 1.7 program for pain, and gentler conditioning agents for use with ExaCell. In the CF franchise, in R&D, and across the business, this quarter, Vertex has continued to make meaningful advancements to bring our CFTR portfolio to more patients around the globe and bring additional first-in-class or best-in-class, potentially transformative medicines to multiple new disease areas. With that overview, I'll turn to the details of recent R&D progress, starting with CF. while Trikafta delivers tremendous benefit for patients. If it's possible to do better, we're committed to being the ones who do so. And that is the goal for our next in class, vanzecaftor triple combination therapy. I'm pleased to share, we expect to complete all three phase three studies, Skyline 102 and 103 in patients ages 12 years and above, and the Ridgeline study in patients ages 6 to 11 by the end of 2023, and release results from these three studies in early 24. We have high expectations from the Vanzecafter triple program to lead to further improvements in CFTR function based on the totality of the evidence generated to date. The most direct readout of higher CFTR function is chloride transport in vitro and sweat chloride in patients. In vitro, our human bronchial epithelial cell assays with the vanzecafta triple showed greater restoration of chloride transport than with Trikafta. And in phase two, in patients, the vanzecafta triple clinical studies showed correspondingly lower levels of sweat chloride than in previous studies with Trikafta. We therefore believe the vanzecaftotriple has the potential to provide patients with enhanced clinical benefit, the convenience of once daily dosing, and additionally, the vanzecaftotriple carries a substantially lower royalty burden. Another important program in our CF portfolio is VX522, our CFTR mRNA therapy in development with our partners at Moderna for the more than 5,000 CF patients who cannot benefit from CFTR modulators. We have enthusiasm for this approach for three key reasons based on what we've achieved to date. First, the delivery of mRNA at high efficiency into HPE cells in vitro. Second, expression of CFTR protein leading to high levels of chloride transport. And third, successful nebulized delivery of mRNA in both small and large animals, resulting in expression of CFTR protein in the desired cells. We continue to enroll and dose CF patients in the single ascending dose or SAD study of VX522. And we expect to complete the SAD portion and initiate the multiple ascending dose portion of the study this year. Turning now to Exacell, our CRISPR-Cas9-based gene editing program for sickle cell disease and transfusion-dependent beta thalassemia, which targets the most severe patients and an estimated patient population of approximately 32,000. Exacell holds the promise to be a one-time functional cure for these diseases. On the regulatory front, the FDA has accepted our filings and granted priority review in sickle cell disease with a December 8th PDUFA date, along with a standard review in beta thalassemia with a March 30th, 2024 PDUFA date. The FDA has indicated an advisory committee will be held, and we look forward to the opportunity to discuss the high unmet need, share results from the XSL studies, and discuss the transformative potential XSL holds for patients. Outside the US, in the EU, and the UK, reviews for our XSL filings are also well underway. Our oral presentation at the most recent EHA meeting in June provided new data that were the basis of the EMA and MHRA regulatory filings. Both trials met the primary and key secondary endpoints with follow-up in some patients of more than 36 months. The XSL-EHA results continue to demonstrate transformative, consistent, and durable benefit for patients as measured by freedom from severe vaso-occlusive crises for 94% of SCD patients and transfusion independence in 89% of TDT patients. The safety profile was generally consistent with busulfan conditioning and bone marrow transplantation. Another significant opportunity for XSL is in younger patients, and the pediatric trials in both sickle cell disease and beta thalassemia are underway. We have enrolled more than half the target number of patients in both pediatric studies and have dosed multiple patients. This is an important area of focus given the opportunity to intervene earlier and potentially prevent organ damage and other complications before they ever occur. As the PDUFA dates approach in the U.S. and reviews come to conclusion in the U.K. and E.U., we look forward to bringing this one-time potentially curative therapy to thousands of patients with severe sickle cell disease and transfusion-dependent beta thalassemia. Turning next to our pain program and VX548, our novel, highly selective NAV1.8 inhibitor that holds the promise of effective pain relief without the side effects or addictive properties of opioids. In a coupane, I am pleased to share that all three Phase III studies, two randomized control trials, and a single-arm safety and efficacy study will complete by the end of this year, with results available in late 2023 or early 2024. The pace of this Phase 3 program has been rapid, which we see as indicative of the high unmet need and strong interest in an efficacious non-opioid acute pain therapy. We have high confidence in the outlook for these Phase 3 studies given, one, the genetic and pharmacologic validation of the target, two, multiple proof-of-concept trials with the predecessor molecule, and with VX548 itself, and three, the similar methodology, design, and endpoints of our Phase 3 studies compared to the Phase 2 program. Closing on acute pain, recall that the Phase 3 program has been designed to support a broad, moderate to severe acute pain label, which would enable prescribing and usage across multiple care settings, including in hospital or the ambulatory surgical center, post-discharge, and in the home. We're also studying VX548 in diabetic peripheral neuropathy, or DPN, a type of peripheral neuropathic pain that represents yet another significant area of unmet need and another multi-billion dollar market opportunity. We've previously delivered positive proof-of-concept data in peripheral neuropathic pain with the predecessor molecule, VX150. The current study in DPN with VX548 is a 12-week phase 2 dose-ranging proof-of-concept study. I am pleased to share the timeline for this DPN study has accelerated, and we have recently completed enrollment. This study will complete by the end of this year, and we expect to share results in late 2023 or early 2024. Moving now to type 1 diabetes, where we're evaluating stem cell-derived, fully differentiated, insulin-producing islet cells for people with type 1 diabetes. Our goal is to develop a functional cure for the millions of people living with type 1 diabetes, including the more than 2.5 million patients in North America and Europe alone. The VX880 program is our foundational cell therapy program for T1D, in which we have already demonstrated proof of concept. In the VX880 trial or the naked cell program, patients take standard immunosuppressants to protect the islets from the immune system. We presented updated clinical data on Parts A and B of the study at the recent American Diabetes Association meeting. The presentation at the ADA showed that all six patients treated with VX880 engrafted islet cells, produced endogenous insulin, and had improved glycemic control while reducing or eliminating exogenous insulin use. Importantly, the two patients with at least one year follow-up saw a complete elimination of severe hypoglycemic events, maintained hemoglobin A1Cs below 7%, and were insulin independent. Further, patients who were earlier on their course of therapy were on a similar trajectory as the two patients with long-term follow-up. Based on these results, the VX880 trial has now advanced to Part C, where patients are treated concurrently at the full target dose. And as part of our global study plan, we've now opened clinical trial sites in Europe, in addition to those already open in the U.S. and Canada. Our second program, VX264, or the Cellsless Device Program, encapsulates these same cells, which have already demonstrated proof of concept in a proprietary immunoprotective device. And hence, there is no requirement for immunosuppressants. I am pleased to share that enrollment in the VX264 study has initiated and we have already dosed the first patient. The third program is our hypoimmune program in which we edit the same fully differentiated cells to cloak them from the immune system. This represents another path to obviating the need for immunosuppressants. In March, we expanded our collaboration with CRISPR Therapeutics into type 1 diabetes to use CRISPR-Cas9 to make these edits, and we continue to make progress in this research stage program. Transitioning now to enaxiplin or VX147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease, or AMKD. a genetically defined disease that affects approximately 100,000 patients in the U.S. and Europe alone. Recall, the Anaxipline Pivotal Program for patients with AMKD is a single, adaptive Phase 2-3 study with a pathway to accelerated approval in the U.S. The Phase 2b dose-ranging portion of the study continues to enroll and dose and remains on track to complete this year. We also continue to work to enhance AMKD disease awareness and genetic testing availability to support diagnosis, including through partnerships with Natera, a leader in genetic testing, and Arcana, a leader in renal pathology services. To close, an update on our Alpha-1 Antitrypsin Deficiency, or AATD program. Our small molecule approach targets both the lung and liver manifestations of this disease that affects an estimated 100,000 people in North America and Europe. Our program is exploring two hypotheses. First, longer treatment duration with VX864, and second, a more potent molecule with VX634. The Phase II program for VX864, a 48-week study in patients with AATD that assesses both liver clearance of Z polymer and functional plasma AAT levels, is ongoing and is anticipated to complete enrollment later this year. VX-634, the next-in-class molecule with multifold greater potency and better drug-like properties, is projected to complete its Phase I trial by the end of this year. Overall, the AATD program remains on track, and we look forward to sharing results in 2024. With that, I'll turn it over to Stuart to provide a commercial update, including details on our launch preparations for XSL.

Thanks Reshma. From a commercial perspective, we had strong second quarter results as we continue our focus on reaching all patients eligible for our CFTR modulators and maintaining high levels of adherence for patients treated with our medicines. In addition, we continue to prepare for multiple potential near-term launches, including Exacell in severe sickle cell disease and transfusion-dependent beta-thalassemia, VX548 in moderate to severe acute pain, and the Vanzecafta triple combination in CF. At the same time, we are developing new capabilities to support the commercialization of other pipeline assets, such as disease awareness for AMKD and investing in our manufacturing capabilities for type 1 diabetes. Given our nearest term opportunity is exocel in haemoglobinopathies, where we have completed our regulatory filings in Europe and the U.S. and also been granted PDUFA dates in the U.S., this quarter I will focus my comments about our pipeline on prelaunch activities for exocel. but briefly first on CF. At the beginning of this year there were more than 20,000 people with CF in North America, Europe and Australia who could benefit but were not yet being treated with a CFTR modulator. We continue to bring our medicines to these patients through new approvals and uptake following additional reimbursements with a focus on reaching younger patients and this will continue to be a driver of near-term growth for our business. Second quarter 2023 CF revenue growth of 14% was consistent with this outlook and was driven primarily by expanded use of our medicines in younger age groups. Following U.S. Trikafta approval in children ages 2 to 5 in late April, we've seen strong interest from the CF community, with the first prescription written just hours after the approval and uptake across all eligible patients. Outside the US, CAF TRIO growth has continued to be strong in patients ages 16 and older, following approval, reimbursement and successful launches in multiple geographies. In addition, we received EU approval for Orkambi in children ages 1 to 2 in early July, and we continue to expect approval for CAF TRIO in the EU in children ages 2 to 5 by the end of this year. We are also actively enrolling our CAF TRIO study in children ages 1 to 2. Overall, we see continued growth for our portfolio of CFTR modulators, driven by approvals, reimbursement, and uptake of our medicines in younger patients. In addition, approvals of future CF medicines will also drive growth. Notably, our next generation, Vanzacafta Triple, seeks to provide improved efficacy for patients and a new treatment option for those who have discontinued prior CFTR modulator therapy. and longer-term VX522, our mRNA approach, could offer a therapy for the more than 5,000 patients who cannot benefit from CFTR modulators. Shifting now to XSL, which holds curative potential for patients with severe sickle cell disease and transfusion-dependent beta thalassemia, both chronic diseases that can be disabling and life-shortening and have an extremely high burden of care. On previous quarterly earnings calls, I provided details for XSL on the estimated eligible patient population, the geographic concentration of those patients, and our proposed ATC network of 50 centers in the U.S. and 25 in Europe, the hiring and training of our field and medical education teams, and insights from physician and patient market research. This quarter, I'd like to provide our perspective on access and reimbursement and our discussions globally with payers and policymakers. Our teams continue to make excellent progress in pre-approval discussions with both government and commercial payers in the U.S. and Europe. With more than a dozen cell and gene therapies on the market, payers across different channels are increasingly experienced with these transformative types of therapies. In the U.S., approximately 65% of patients with sickle cell disease or beta thalassemia have coverage through government programs, with the majority via Medicaid, and the remaining 35% of patients are covered by private insurance. Our teams have already engaged Medicaid administrators in all 50 states, with a particular focus on the 24 states with the highest prevalence of sickle cell disease, accounting for an estimated 90% of Medicaid patients with SCD. We're encouraged by the enthusiasm from state Medicaid administrators for Exacell, as well as the proactive steps they are taking to prepare for the availability of therapies like Exacell, including the enablement of separate payment policies for coverage of the cost of the therapy, distinct from the cost of the bone marrow transplant procedure. The Medicaid-focused CMS cell and gene therapy access model also continues to make progress towards its anticipated launch in 2026. The model is clear evidence of the federal government's recognition of the potential transformative value of gene therapies like Exocel to treat sickle cell disease and their interest in finding innovative payment solutions and pathways for state Medicaid programs. Shifting to commercial payers, we have had high levels of engagement with commercial payers, including the top four payers that account for approximately 80% of commercial lives. And our goal is to facilitate timely coverage decisions upon a potential XSL approval. Our pre-approval discussions have been encouraging and have focused on disease burden, epidemiology estimates, our clinical data, and potential payment models. In Europe, the MAA reviews are well underway, and thus we are also working on paving the way to secure reimbursed access for patients in our targeted European markets. We have been engaging with health systems to educate them on the significant disease burden on patients, healthcare systems, and society. In addition, we have been meeting with European health authorities to understand their interest in different payment models and to communicate the holistic value of a one-time potential functional cure. Given the urgent, unmet need for new treatments for sickle cell disease and beta thalassemia, there is significant interest from patients and physicians, particularly in geographies with high concentrations of the eligible patient population. To conclude, it's a remarkable time to be at Vertex. We continue to make progress treating more CF patients, while our excitement for the transformative promise of XSL for patients and the resulting multi-billion dollar market opportunity continues to grow as we approach potential approval. We are also preparing for multiple additional near-term launches, including the Vanzacafta Triple in CF and VX548 in acute pain, both of which have the potential to dramatically improve patients' lives. I'll now turn the call over to Charlie to review the financials.

Thanks, Stuart. Vertex's excellent results in the second quarter of 2023 demonstrate once again our consistent, strong performance and attractive growth profile. Second quarter 2023 revenue increased 14% year-over-year to $2.49 billion. Growth was led by a 26% year-over-year increase outside the U.S. on continued strong uptake of Trikafta Keftrio, in markets with recently achieved reimbursement, as well as label extensions in younger age groups. Similarly, expansion in younger age groups helped drive 7% U.S. revenue growth following the recent FDA approval of Trikafta in patients ages 2 to 5. Second quarter and first half revenues also benefited from increases in channel inventory in certain international markets, which are expected to draw down in the second half. Second quarter 2023 combined non-GAAP R&D acquired IP R&D and SG&A expenses were $1.04 billion compared to $750 million in the second quarter of 2022. Q2 2023 results include $110 million of acquired IPR&D charges compared to $62 million of such charges in the second quarter of 2022. Second quarter 2023 IPR&D expense reflects a $70 million milestone to CRISPR therapeutics for progress made in our hypoimmune program for type 1 diabetes. Aside from our investments in external innovation and the resulting higher acquired IPR&D charges, operating expense growth was driven, as expected, by continued investment in research and our advancing pipeline, which includes mid- and late-stage clinical assets across eight different disease areas. The most significant areas of increased investment versus prior year included the clinical studies for the Vanzacafta triple NCF, for VX548 in acute pain, and for type 1 diabetes. In addition, we continued our pre-commercial activities for Exacel and other anticipated near-term launches. Given the potentially transformative benefits to patients and multibillion-dollar market opportunities for our mid- and late-stage programs, we will continue to invest appropriately. Second quarter 2023 non-GAAP operating income was $1.15 billion compared to $1.19 billion in the second quarter of 2022. Second quarter non-GAAP earnings per share were $3.89, representing 8% growth compared to $3.60 in the second quarter of 2022. We ended the quarter with $12.6 billion in cash and investments. Now switching to guidance. Given our strong first-half results and our consistent execution, including the successful launch of Trikafta in patients ages 2 to 5 in the U.S., we are increasing our 2023 revenue guidance as detailed on slide 16. For the full year 2023, we now expect CF net product revenue of $9.7 to $9.8 billion, an increase of $100 to $150 million compared to our prior range of $9.55 to $9.7 billion. Note that this revenue guidance includes an expected approximate 150 percentage point headwind to our revenue growth rate, consistent with our prior expectations. In addition, given our December 8th U.S. PDUFA date for exocel and sickle cell disease, 2023 product revenue guidance continues to reflect revenue from cystic fibrosis products only. We are also raising our 2023 guidance for combined non-GAAP R&D, acquired IP R&D, and SG&A expenses to a range of $4.1 to $4.2 billion, an increase of $200 million from prior guidance. This increase reflects higher IP R&D expenses from new business development, including collaborations with Entrata in DM1 and with CRISPR in type 1 diabetes. Our 2023 non-GAAP operating expense guidance now includes approximately $500 million of upfronts and milestones compared to the $300 million projected at the start of the year. We continue to invest a majority of our operating expenses into R&D, given the momentum in our multiple mid- and late-stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion-dollar opportunities represented by our programs with near-term launch potential, while continuing to leverage an attractive business model afforded by our focus in specialty markets. Our guidance for projected full-year 2023 non-GAAP effective tax rate of 21% to 22% is unchanged. In closing, Vertex delivered excellent results for the second quarter of 2023. We delivered strong revenue growth, completed important regulatory milestones, updated on significant clinical trial programs, and invested internally and externally. As we continue to advance our programs in 2023, we anticipate further important milestones as highlighted on slide 17 to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

Thanks, Charlie. Gary, can you please cue the first question?

We will now begin the question and answer session. To ask a question, you may press star, then 1 on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then 2. Our first question is from Phil Nadeau with Cowan & Company. Please go ahead.

Phil Nadeau Good afternoon. Thanks for taking our questions. Just a couple on XSL. In the prepared remarks you mentioned, or at least in the press release you mentioned, that an advisory committee is likely Does Vertex have any sense of what is likely to be discussed or debated at the advisory committee? And then second, for Stuart, thanks for all your comments on the commercial prep. We have seen gene and cell therapy launches get off to relatively slow starts of late, with some not actually having patients dose for seven or so months after approval. What does Vertex learn from that? What could you do to increase the speed at which patients are adopting XSL post-approval? Thank you.

Good afternoon, Phil. This is Rachel. Let me take the first part of your question, and then I'll ask Stuart to comment on the commercial launch readiness. With regard to XSL, the FDA has informed us that there will be an advisory committee. This is not unexpected, as we've discussed in the past, given the new mechanism of action. We don't have further details. Those will be forthcoming. And I expect we'll know more as we approach the date of the ADCOM, which we don't have today either. However, conventionally, the advisory committees usually take place about one to two months before the Purdue for date. So that's the general framework that we're looking at. We are very excited to have the opportunity to share our data. to talk about the benefit-risk and to talk about the transformative potential and to have the patient's voices heard at the advisory committee. Let me turn it over to Stuart to comment on launch readiness.

Yeah, Phil, so thanks for the question. Obviously, the first most important step to provide the conditions for a successful launch are going to be to secure access and reimbursement. Because as you know, without access and reimbursement, there really is no opportunity for patients to get treated. And that's why I focus my comments on that. And we are doing everything we can with payers, both in the US and internationally, to try and get access and reimbursement as close to regulatory approval as we possibly can. Obviously, that's not entirely within our control, but that's what we're working on. In terms of the kind of uptake curve in the future, Obviously, that's going to depend on the interest from physicians and patients. We know that that is very high. But I would remind you that, as I've said on previous calls, we do expect the uptake with XSL to be slower, obviously, than we see with our CF medicines where the launches are, you know, almost vertical. And that's largely because, as you know, this is a multi-month process that a patient has to go through to get treated with XSL. Obviously, they have to decide with their physician that they want to go through a gene therapy. They have to have their cells collected. The cells then have to be edited, returned to the site, and then the patient has the schedule coming in for essentially the equivalent of a bone marrow transplant before they're actually dosed with the X-cell drug product. So it is a multi-month process from start to finish for any individual patient. And so that's why we've always said this launch we do expect to be slightly slower in uptake rate than in cystic fibrosis. But we continue to believe there's a lot of interest. It's a big market opportunity, and we see XSL as a multibillion-dollar opportunity in the future.

Great. One follow-up, if I might, on the reimbursement. We've seen warranty agreements put in place by one recent gene therapy launch. Is that something you're considering or you think would be helpful?

Sorry, Phil, I didn't quite catch the question. Can you say it again?

Yeah, in terms of reimbursement in the structure of reimbursement agreements, one recent gene therapy launch included a warranty as part of the reimbursement agreement. Is that something Vertex is considering or would think would be helpful for a launch like XSL?

Yeah, we are considering a range of different options, Phil. The reason for that is If you ask one payer what they're looking for, you get one answer. If you ask another payer, you get another answer. So I think much as we've done with cystic fibrosis, we're going to look to be flexible. There are some who are going to be interested in just a straight price and just paying up front for the benefits for one-time functional cures. Others are looking at more things like outcomes-based agreements and that. And so right now we're in kind of listening mode and defining and designing options. what the nature of our payment models will be, but I think the key word is probably flexibility.

Perfect. Thanks for taking our questions, and congrats on the progress.

The next question is from Lisa Baco with Evercore ISI. Please go ahead.

Hi there. Thanks for taking my question, and congratulations on the good quarter. I'm just wondering if you could give us a view on sort of the next data readout for your Type 1 diabetes program, both the CELS and CELS Plus pouch. Thanks.

Sure thing. Lisa, with regard to the T1D program, on the VX880 side, that's the, let's call it the naked cells program. You should expect to have a data readout at the fall diabetes conference where there will be an oral presentation. On the 264 program, that's the cells plus device program, we've just initiated enrollment. We've just dosed, as you heard in my prepared remarks, the first patient. And you should expect to hear from us with regard to results from that cells plus device program, which does not require immunosuppressants, either when we've reached a milestone in terms of data readout, or we have a decision to communicate. We won't be sharing results patient by patient.

Okay, fair enough. And then, As you think about your kind of commercial path for pain, are you going to be focusing on certain types of centers? I mean, this could be obviously a very broad market and opportunity. How are you thinking about the rollout and where, you know, I'm curious on that kind of thing. The market estimates could be, you know, have a very wide range depending on how you think about it. Thanks.

Sure. Lisa, you're right. We see this as an enormous opportunity. Let me ask Stuart to tell you how we plan to approach that opportunity. Stuart?

Yeah. So acute pain, obviously, which is going to be our first launch indication, subject to the studies being positive, is Two things can be true at the same time, Lisa, I'd say. One is acute pain therapies are prescribed by a wide range of prescribers. That is indeed true. But it's equally true that a large percentage of the prescriptions are concentrated in institutions, ambulatory surgical centers, settings like that, where patients are either prescribed and dispensed their acute pain medicine while they're in the institution or the facility. And then they're also prescribed and given a prescription on discharge for their ongoing pain management when they leave the facility. That accounts for a large percentage of the prescriptions in acute pain. Those prescriptions are concentrated in somewhere around just shy of 2,000. sites covered by about 220 or so IDNs, and that is going to be the primary focus of our commercialization activities. We think we can cover that universe of centers with a sales force approximately in the 150 range, which fits very nicely with our focus on specialty markets.

Thanks.

The request of management, could we please limit yourselves to one question, and if you have a follow-up, please press star 1 to rejoin the queue. The next question is from Salveen Richter with Goldman Sachs. Please go ahead.

Good afternoon. Thanks for taking my question. Just a follow-up on the acute pain program. Just can you help us understand, apart from, you know, upon a positive data outcome here, And, you know, given the target prescribers you mentioned, what needs to be done logistically to ensure a successful launch with regard to, you know, just the marketing aspect, whether there's kind of any, you know, any understanding that needs to be played out with regard to contracts and how the no pain law kind of falls into this. Just any idea of how you can ensure this plays out well. Thank you.

Sure, Salveen, I'll ask Stuart to comment.

Yes, Salveen, thanks for the question. I think there's a couple of other things that are likely to be supportive of the X548 in acute pain. One is I think we are likely to see a number of the existing pain treatment guidelines consider updates to their guidelines once there is the availability of a safe and effective non-opioid medicine. In addition, and you mentioned one of them, I think we are increasingly going to see policies change their focus. The policies that have been put in place in states and hospitals over the last few years for understandable reasons have largely all been about restricting prescriptions, restricting who can prescribe for which patient types for what length of time. I think we are beginning to see the focus of those policy initiatives change to being supportive of of non-opioid pain medicines like VX548. And I think that that's a very welcome systemic change which will potentially support the uptake of VX548 subsequent to it getting approved. So in addition to our own commercialization efforts, I think there's a number of other things which would be supportive of the launch.

The next question is from Jeff Meacham with Bank of America. Please go ahead.

Hey, guys. Thanks for the question. Just had a follow-up on XSL. I know you guys are focused today on regulatory and commercial as well, but when you think about the improved conditioning regimen, I wanted to know kind of what we should expect from that, optimization of that. What does success look like, I guess, for that, and what are the timelines I think that we'll see some data for?

Sure. Jeff, as we think about the busulfan-based conditioning regimen, which is what XSL will launch with, We see that as having a positive benefit-risk profile for the approximately 32,000 people with the most severe forms of sickle cell disease and beta-falcemia. And with the improved or gentler conditioning, we see the opportunity to serve the full 150,000 people with sickle cell disease and beta-falcemia in Europe and the U.S. What this program looks like, and we have an active set of programs internally. Our partners at CRISPR are working on this problem. Other academia and biotechs are working on this problem. And so I do see this as a problem that will be solved. It's not a tomorrow solution, but I see this happening in the coming months and years. What we see is the opportunity to have a conditioning regimen that very specifically targets the compartment and the cells that are limited to those hematopoietic stem cells, sparing all of the other cells, and in so doing, not have the side effects of busulfan, including the very significant cytopenias that you see with busulfan. So I do think that this is an area that we will see a solution for because we and others are working on it and because of the broad application, and I do think you'll see progress in the coming months and inner years. I don't mean decades.

Thank you. Our next question is from Robin Karnowskis with Truist Securities. Please go ahead.

Hi, sorry for the noise. I'm on board a plane and we're departing. So the question is, what does the bar for neuropathic mean? I know your previous study with your previous drug kind of looks similar to Lyrica. Maybe you could set that for us in seconds. You know, we've done some due diligence, and the chemo-related peripheral neuropathy is a huge unmet need. I wanted to know whether you thought it might work in this population as well. Thanks.

Yeah. So, Robin, the bar for neuropathic pain is to have a better overall profile, benefit-risk taken together than existing therapies. As you know, the existing therapy has limitations in terms of efficacy, but there are also limitations on the safety-slash-AE side. And the reason for that is what we use for neuropathic pain is, frankly, a recycled medicine that that comes from fundamentally central nervous system depression that we're reusing for neuropathic pain because that's the best we have. So what we're going to be looking for is improvement in diabetic peripheral neuropathic pain scores, change from baseline, And our Phase II dose-ranging proof-of-concept study also has a Lyrica arm for context. So we'll be able to see the magnitude of the treatment effect as well as a Lyrica arm for context.

The next question is from David Reisinger with Lyric Partners. Please go ahead.

Yes, thanks very much. I wanted to change gears, please, to your two AAT candidates. Could you frame the efficacy results to watch in 2024 and potential timelines for those readouts next year? Thank you.

Sure. David, I think you're asking about the AATD program. And just to ground everyone on that one, This is our program where we have two molecules, VX864, which is in a Phase II study, and VX634, which is making its way through a Phase I study. Our excitement for this particular program and disease comes from the fact that it fits the vertex strategy like a glove. We are seeking to target both the liver and lung manifestations of this disease, and our small molecule approach is the only one that holds the potential to treat both liver and lung manifestations. You need to treat both in order to have a transformative medicine. Our VX864 study, which is in Phase 2, is a long-term study. It's a 48-week study. And there we are looking at the impact of long-term dosing on both functional AAT levels in the blood and clearance of liver polymer. You might recall that on a post-hoc analysis of our VX864 Phase II data from a few years ago, we saw a 90-plus percent reduction in serum Z polymer levels, which is why we're so interested in the liver polymer levels. And in the 634 study, we are going through our first in human studies. So I expect that we'll have all the results from both of these trials by sometime next year, so 2024. and I expect that we'll be able to share the results at that time. Exact timing, we're going to need to get a few more months under our belt to look at the enrollment dynamics, but I do expect we'll be sharing results by sometime next year. So it's a 24 milestone.

Thank you. The next question is from Terrence Flynn with Morgan Stanley. Please go ahead.

Hi, thanks for taking the question. Stuart, you mentioned there were about 20,000 patients not on drug at the start of the year that could potentially be eligible. Just wondering where that figure will end, assuming you achieve your new 2023 guidance. Thank you.

Yeah, Terrence. So we've kind of gone away over the last few years of kind of giving detail to the forensic accounting of all the different patient numbers. And so I'm not going to kind of give you a an updated estimate at this time. But as Charlie said in his remarks and I said in mine, we've continued to make good progress in treating more patients, including in younger age groups and including in other countries where we've secured reimbursements and launches. But other than that, we're not going into more detail at this time. We may, if there's a substantial change, we may update Those numbers as we've done in the last couple of years also At the beginning of next year when we talk about our guidance for the following year The next question is from Mohit Bansal with Wells Fargo, please go ahead Thank you for taking my question just wanted to

get some color on how do you – so, Zresha, you talked about sweat chloride improvement with the lensocaster trial. Is there a correlation between the amount of sweat chloride you reduced versus the SUV improvement? If I'm not mistaken, the sweat chloride improvement was about 30% more than the Trikafta combo with this combo. So, just trying to understand how should we think about the bar for FEV that this new combo will set. Thank you. Yeah.

Well, I think you're talking about the Vanzacaptor triple. That's our next in class regimen for CF. This is the program that's in phase three, and we expect to complete both studies in the 12-plus-year-old age group and the six-plus-year age group this year with results from that pivotal program early next year. With regard to your question on sweat chloride and PPF1, yes. There is a very strong association between improvements in sweat chloride and improvements in lung function. And you can see that across all of our previous CFTR modulators, all the way from Kalydeco through Orkambi, Sim, and Trikafta. So that relationship is strong. In terms of what you should expect from the Vanzacaptor Triple, or let me put it another way, the reason we have such high enthusiasm for the Vanzacaptor Triple In the preclinical experiments, including the very important HBE assays, which have been not only qualitatively predictive but quantitatively so, the vanzecaptor triple, I know this is hard to believe in a tall order, but the vanzecaptor triple preclinically is even better than tricaptor in our HBE cells. And when we look across the Phase II studies that have been done, the vanzecaptor triple has better sweat chloride than than even Trikafta. It's hard to make a call on PPFEV1 because in the Phase II studies, the sample sizes are obviously smaller, and PPFEV1 is a more variable endpoint. So I think the right measure to look at is indeed sweat chloride, and from all of the data we've collected, VANSA is even better than Trikafta on that measurement of sweat chloride.

Helpful. Thank you. The next question is from Michael Yee with Jefferies. Please go ahead.

Hey, guys. Thanks for the question. You announced that the chronic pain, neuropathic pain study phase two was complete enrollment, so that's super exciting, and the data, I guess, is end of 23 or early 24. Can you talk a little bit about, I guess, on one side, you feel confident because of the biology and the acute data was also quite strong, and there's also some early chronic data as well with the last gen. but also, I guess, historically, chronic pain studies can be challenging with placebos. Even with Vicodin and opioids, you can get mixed results. So I just wanted to ask about your confidence around this probability success versus the acute study and how we should take this study into consideration from an expectation standpoint, give us just a phase two. Thanks, Reshma.

Sure. My confidence level in the VX548 program is equal for the acute pain studies in that Phase III program as it is for the diabetic peripheral neuropathy Phase II program. And you're right, that confidence comes from the pharmacologic validation of the target, which we ourselves conducted with our predecessor molecules BX150, and also the genetic validation of the 1A target. With regard to a double-click on what you could expect from both acute and the neuropathic pain studies, the acute pain program is two randomized clinical trials in the same bunionectomy, abdominoplasty. Those are two of the RCTs. And the third is a single-arm safety and efficacy study to allow a broad moderate to severe acute pain label in the various settings that Stuart described in terms of use. And I expect that those results will be available late this year, early next. And the goal there is, gosh, if we see what we saw in phase two for VX5 for acute pain, that would be a home run. So the diabetic peripheral neuropathy program, this is a multiple dose, dose ranging proof of concept study where we also have a gabapentin arm for context. So what you should be Looking for there is improvements in the pain score from baseline to the 12-week time point when we have the pain endpoint, and you'll be able to make assessments versus the gabapentin arm that's in there for context. That study is fully enrolled and should also be available in terms of results late this year, early next year.

The next question is from Evan Siegerman with BMO Capital Markets. Please go ahead.

Hi, guys. Thank you so much for taking my question. Kind of a follow-up to Mohit's question on the Vanda Triple. Talk about what the added benefit of the Vanda Triple needs to be versus Trikafta to get patients to switch. You also mentioned, you know, getting patients to levels of carrier levels of sweat chloride. Could you ever get to a wild-type level of sweat chloride? Thank you.

Yep. Let me take the second half of your question, Evan, and then I'll turn it over to Stuart to talk through how we're seeing the commercial opportunity for the vans at Triple. So when you look at parents, so carriers of the CF mutation for those who don't have disease. When you are at those carrier levels of sweat chloride, you have virtually no manifestation of disease. That's why we're targeting carrier levels of sweat chloride. You're fundamentally just like you and me, I'm not a carrier and I'm not a patient with CF, but if you are a carrier of CF, you are fundamentally unaffected. That's why that's the highest bar to achieve and that's why that's the bar that We continue to chase. The Trikafta triple gets some patients there. The Vanzecafta triple will get more patients there. But our research continues, and we've already identified additional potentiators and correctors that will get us to that ultimate goal of carrier levels of sweat chloride. Stuart?

Yeah, so in terms of the sort of uptake and what's attractive at the profile, we know from speaking with CF clinicians that if has the sort of profile that Reshma described earlier where it's delivering increased levels of benefit in terms of CFTR function as measured through sweat chloride, that that in and of itself will be an attractive proposition because, as Reshma said, the link between increases in CFTR function and improvements in outcomes has been demonstrated through our own work. In addition, you were talking about patients potentially transitioning. I do think there's an important group we should also consider, which is there have been a number of patients who over the years have discontinued their CFTR modulators. It's probably somewhere north of 6,000 patients who we know want to be on a CFTR modulator but have had to discontinue over the years. And I do think that's another population who will welcome an additional treatment option being available.

The next question is from Colin Bristow with UBS. Please go ahead.

Hey, good evening, and congrats on the quarter. Maybe one of the CRISPR-based DMD program. Are you still on track to file the IMD in the second half? And then assuming all goes to plan, would it be reasonable to expect some clinical data in 2024? And then maybe if I could just have a quick follow-on to the vancocaster triplet question, just what do you think you need to see for this to be a... a launch that has a major component of switches versus just a new patient acquisition launch. Thank you.

Colin, I think there are two separate questions in there, one about the VAMSA triple and what do we need to see, and then one on DMD. Let me tackle the DMD, DM1 question, and I'll come back to VAMSA. On the DMD question, I'm going to broaden it out to muscular dystrophies as a whole, and I'll talk about DMD and DM-1. We have programs in DMD that are going through IND-enabling studies now, as well as in DM-1. We actually have multiple programs in DM-1. The lead program is the one that we in-licensed from Entrada. And that program also is already in IMD enabling studies, and both of them should have those results in this second half of 23. And our timing remains to file the IMD for both DMD and for DM1 for the lead program in DM1 in the second half of this year. With regard to the VANZA program, I think Stuart just covered that. What we're looking to see and the way the study is designed is VANZA-CAFTA in the Phase III program head-to-head versus Trikafta, and the primary endpoint is sweat chloride. And the reason for that is Again, with patients with carriers, those who have one CF gene, they have virtually no manifestations of disease. And that is measured, assessed by sweat chloride. Carrier level is a description of sweat chloride levels. So that's what we're measuring. We are, of course, going to have PPFEV1 in there. And as Stuart said, if the profile is, as I describe it to be, improvement on sweat chloride levels, we expect it to have real value to patients. I'll also add that the vanzecafta triple has a lower royalty burden than the tricafta combination.

Thanks, Reshma. Thanks, Colin. Gary, that brings us to time. Could you close us out, please?

This concludes the question and answer session, and the conference is also now concluded. Thank you for attending today's presentation. You may now disconnect.